Method of diagnosis and treatment and related compositions and apparatus

ABSTRACT

A method for treatment of a disease comprising vasospasm or other symptom alleviable by smooth muscle relaxation and a vasodilator delivery system. The figure is a TCD of MCA post nitroglycerine spray obtained during continuous monitoring.

[0001] This application is a Divisional of U.S. Ser. No. 101,934 filedJul. 13, 1998, now U.S. Pat. No. 6,258,032 classified in U.S. Class600/454 and International Class A61B 008/06; and claims priority ofprovisional patent application 60/010,881 filed Jan. 31, 1996 and ofPCT/US97/01576 filed Jan. 29, 1997.

BACKGROUND OF THE INVENTION

[0002] I. Field of the Invention

[0003] This invention deals with medicine and the diagnosis andtreatment of certain types of blood vessel diseases and a variety ofdisorders which all have been discovered to have in common a conditioncalled “Vasospasm” or “Narrowing of the Blood Vessels.”

[0004] II. Description of Prior Art

[0005] The most relevant prior art appears to be:

[0006] 1. Roger P. Woods, Marco Iacoboni, M.D., Ph.D., and John C.Mazziotta, M.D., Ph.D.; Brief Report: Bilateral Spreading CerebralHypoperfusion during Spontaneous Migraine Headache. N Engl J Med 1994;331; 1689-92.

[0007] 2. M. Hennerici M.D., W. Rautenberg, M.D., G. Sitzer, M.D., andA. Schwartz, M.D.; Transcranial Doppler Ultrasound for the Assessment ofIntracranial Arterial Flow Velocity—Part 1, Examination Technique andNormal Values; Surg Neurol 1987; 27; 439-48.

[0008] 3. U.S. Pat. No. 5,309,923 to Leuchter and Cook, U.S. Pat. No.5,307,807 to Sosa et al, U.S. Pat. No. 5,287,859 to Erwin describe“qEEG” devices and techniques useful with the invention.

[0009] 4. U.S. Pat. No. 5,163,444 to Braverman discusses the P300 brainwaves mentioned below.

[0010] III. Problems Presented by Prior Art

[0011] Prior treatment regimens have generally focused on the acutedisease while the present invention embodies the discovery that thevasospasms and vascular narrowings are commonly chronic in nature.Further, past dosages have often been excessive and such over-dosagesare found by applicant's investigations to actually be harmful inpatients at some stages, because such dosages can themselves subtletypromote vasospasms.

SUMMARY OF THE INVENTION

[0012] I. General Statement of the Invention

[0013] It is an object of this invention to treat vascular spasm asidentified primarily from ultrasound, but which may be suspected on theclinical grounds, with the use of vasodilators in a progressivestep-wise fashion, preferably titrated against continuing testing. Theintroduction usage of the medications and tapering of the medicationsmust be done in a specific fashion in order to result in a clinicalimprovement of the patient in a variety of conditions which all have incommon the presence of vascular spasm. Certain of these conditions havenot previously been identified as having vascular spasm as a componentof their disorder, and these conditions have been identified inapplicant's clinical practice and thus will be named further under thesection that deals with claims. It has been recognized that patientswith vascular spasm have a typical clinical presentation of symptoms,and that these symptoms follow a progression in substantially directcorrelation to the vascular spasm identified on Transcranial Doppler(TCD), a technique using ultrasound imaging of the brain for evaluationof vascular size. It is further recognized clinically that vasculardilation medications may have paradoxical responses depending upon dose.In essence, there is a therapeutic window, a dose which is the properdose for treatment of the condition which changes over time. Initiallyunder dosing the patient will result in no change of their symptoms, aswell as overdosing the patient will result in the exact same symptoms asunder dosing the patient or giving the patient no medication at all.Thus vascular dilation medications tend to have a paradoxical responsewith overdose. The proper dosage for a patient is based upon clinicalresponse in association with objective data as may be identified fromTranscranial Doppler ultrasound as well as other imaging modalities.

[0014] Essentially the preferred methodology is to obtain an image ormeasurement of the intracranial blood vessels in the diseased conditionsto be noted under claims, and then introduce low dose vasodilationmedications. Repeat ultrasounds or other imaging modalities are used totitrate the patient's medical response. As vascular dilatation occurs,medications hen become altered in a stepwise tapering fashion, usingultrasound or other imaging modalities to identify the redevelopment ofvasospasm and the appropriate dosage of medication. It is recognizedthat patients' metabolism may vary across the course of the time thatthey are on these medications, and it is further recognized thatpatients' clinical symptoms may not be a useful guide to their responseto medication. Accordingly, repeat evaluations with the use of imagingmodalities are used to assess pharmacological response.

[0015] The invention comprises a method of treating a patient presentingwith symptoms suggestive of a stroke or multiple sclerosis (MS) and/orreporting trauma to the neck and/or head e.g. whiplash or concussionfrom a fall or any other disease discovered to be alleviatable byrelaxation of smooth muscle or to comprise vasospasm, preferablyintracranial vasospasm as a symptom; comprising in combination:

[0016] a) testing by determining rate of blood flow, preferablyintercranially or in the arteries of the neck and or upper back, and/ordetermining relative diameter of those vessels e.g. by magneticresonance imaging (NMRI) and/or determining evoked potential;

[0017] b) treating the patient with an effective dosage of avasodilator, preferably nitroglycerin administered by patch, preferablyat a rate less than about 0.8 mg/hr;

[0018] c) re-determining said rate or diameter or potential(collectively “blood flow”) after said treatment, to evaluate recurrenceof vasospasm;

[0019] d) adjusting the dosage in response to the results of there-determining;

[0020] whereby symptoms comprising headache, burning sensation or painin the head dizziness, or fainting, etc., or other symptoms of thedisease treated, are alleviated.

[0021] Disease:

[0022] The technique and associated compositions are valuable in thetreatment of any condition in which vasospasms, preferably cerebralvasospasms are detected as a component, including without limitation,those conditions listed under Utility of the Invention.

[0023] Symptoms:

[0024] The common symptom to all these conditions is the vasospasm,particularly cerebral vasospasm.

[0025] Testing:

[0026] Transcranial Doppler is the most preferred test, both fordiagnosis and also for titrating dosage of the vasodilators preferredfor treatment. Other tests will preferably be used as discussed underMethodology. Generally intracranial blood velocities greater than 0.6meters/second, are indicative of vasospasm. Generalized cerebralvasospasm is identified by TCD Mean Flow Velocities (MFV) of greaterthan 0.1, more preferably than 0.3 and particularly greater than 0.4meters/second in intracranial vessels (about 0.07, 0.2 and 0.4meters/second, respectively, for vertebrobasilar system) and prolongeddiastolic flow component in which continued elevation of diastolic flowbeyond end diastolic velocity occurs throughout substantially the entirecourse of diastole. This prolonged diastole is the most preferredindicator of vasospasm. Other presently available tests which arevaluable for vasospasm detection and dosage titration comprise SPECTnuclear medicine testing, angiograms, EEG, qEEG, P300, and otherneuropsycological, psychological and electrophysiological tests whichcan monitor mental impairment due to vasospasm.

[0027] Vasodilator:

[0028] Nitroglycerine is the most preferred vasodilator for thetreatment of the invention, both because of its ready availability in avariety of forms; pill, patch, ointment, cream, spray, inhaler, etc.,and because its pharmacology is so well known. The many Nitroglycerineequivalents and substitutes, such as p.o. clonidine, Dynacirc(isradipine), hydrazine, or long acting nifedipine and others known tothe art, can be used to replace or to supplement Nitroglycerine. Forpatients exhibiting Nitroglycerine intolerance, a combination ofNitroglycerine (spray or patch) with Nifedipine is particularlypreferred.

[0029] Alpha blockers have been tried. Hytrin (Terazosin) has not beenfound to be effective. Catapress (Clonidine) has been extremelyeffective. Minipress (Prazosin) has been significantly effective andfrequently better tolerated in the long run than Clonidine, although inApplicant's patients, it seems to treat the problem successfully enoughto prevent the symptoms, but not enough to allow complete resolution ofthe vasospasm. Cardura (Doxazosin) has been a relatively mildmedication. Aldomet (Methyldopa) has been useful in some patients.Reserpine has been an extremely effective medication. In the short term,it is helpful due to the parasympathomimetic effect, which tends todecrease the activity of the Sumpathetic nervous system. Later, itsdirect sympatholytic action is very effective. Frequently, a dose needsto be adjusted downward approximately 6-10 weeks after institution oftherapy. It has even been useful in treating migraine induced depressiondue to chronic vasospasm with or without headache in those patients whocould not tolerate other vasodilators. Clonidine has also been useful inthese depressed patients who could not respond to other vasodilatingmedications.

[0030] ACE inhibitors are effective. With use of ACE inhibitors andconcomitant administration of low dose Nitroglycerin, {fraction(1/10)}th inch once a day to several times a day, most patients may beeventually weaned from the use of oral medications, although Applicantdoes tend to maintain them on low dose Nitroglycerin in perpetuity.Other Angiotensin Converting Enzyme Inhibitors, including Capoten(Captopril), Altace (Ramipril), Lotensin (Benazepril), Monopril(Fosinopril), Prinivil (Lisinopril), Vasotech (Enalapril), and an ACEinhibitor have also been tried. Applicant suspects that ACE inhibitorswork the best due to their activity on the Nitric Oxide pathway. Theyare most effective at reversing the vasospasm when used in conjunctionwith low dose nitrates.

[0031] Calcium channel blockers are effective. The most effective hasbeen Dynacirc (Isradapine). Much less effective have been, in descendingorder of effectiveness, Nifedipine, Nimodopine, Plendil (Felodipine),Dilacor (Diltiazem), Cardene (Nicardipine) and, Norvasc (Amlodopine) andfinally, Verapamil.

[0032] Other agents that deserve special mention include Toradol IM indoses of 90-120 mg. In lower doses, this is not so effective.Unfortunately, due to the new FDA guidelines, Applicant no longer usesthis medication in these doses. Hydralazine is effective, but tends tocause significant blood pressure changes in these patients.Interestingly though, Hydralazine tends to improve the morphology of thediastolic flow component dramatically, which in view of Hydralazine'seffect on arterioles, bolsters the perspective that the diastolic phaseof the Transcranial Doppler is a good indicator of downstream runoff.

[0033] Psychiatric agents frequently have vasoactive effects. Prozac,and other non-vasoconstricting medications are helpful.

[0034] As examples of the many drugs available: Clonidine has beenextremely effective. Hytrin (Terazosin), Ismelin (Guanethidine),Minipress (Prazosin), have been all tried, with less successful results.Cardura (Doxazosin) is still being tried, but initial results are justnow coming available. Dibenzyline (Phenoxybenzamine) beta blockers,Inderal (Propranolol), Tenormin (Atenolol), Normodyne (Labetolol),Lopressor (Metoprolol) Imitrex (Sumatriptan), IM Toradol (Ketoralac)Channel Blocker, and an ACE inhibitor along with low dose Nitroglycerineand a Clonidine patch, as well as magnesium, Brethine, etc.

[0035] Accupril (Quinapril), Altace (Ramipril), Capoten(Captopril),Lotensin (Benazepril), Monopril (Fosinopril), Prinivil (Lisinopril),Zestril (Lisinopril timed released), Univasc (Moexipril), Vasotec(Elalapril), Cozaar (Losartan). Accupril (Quinapril) has Inderal(Propranolol), Tenormin (Atenolol), Normodyne (Labetolol), Lopressor(Metoprolol) Angiotensin Converting Enzyme Inhibitors (ACE) inhibitorshave been tried including Accupril (Quinapril), Altace (Ramipril),Capoten(Captopril), Lotensin (Benazepril), Monopril (Fosinopril),Prinivil (Lisinopril), Zestril (Lisinopril timed released), Univasc(Moexipril), Vasotec (Elalapril), Cozaar (Losartan). Accupril(Quinapril) has consistently been the most effective. p.o. clonidine,Dynacirc (isradipine), hydrazine, Adalat (Nifedipine) in standard dosesand timed release dosages has been helpful but as a second line drug.Careen (Nicardipine), Nimotop (Nimodopine), Cardizem (Diltiazem),Norvasc (AmlodipineMellaril (Thioridizine) has not been effective.Thorazine Chlorpromazine) has been moderately effective. Navane(Thiothixene) has been extremely effective.

[0036] All of the effective medications have the common characteristicof causing smooth muscle relaxation and reduce pulmonary capillary wedgepressure in most cases, which empirically defines a class of usefulmedications which also includes many other medications, some of whichare setforth in Appendix A, filed with this application.

[0037] Dosage:

[0038] It is an important feature of the invention that the vasodilatordosage is substantially lower than dosage usually prescribed fortreatment of coronary disease, preferably about 1 to 40%, morepreferably 5 to 30, and most preferably 10 to 25% of such conventionaldosage. Based on a 70 kilogram patient, on a Nitroglycerine-equivalentbasis, about 0.001 to 5000, more preferably about 0.01 to 1000 and mostpreferably 0.01 to 20 milligrams per day of vasodilator will be optimalin most cases. Still lower rates will be employed on pediatric, andlower body weight adult, patients. Stated differently, from about 10minutes to 20 hours or even more per day of application of a commercialNitroglycerine patch can be administered during initial treatment.Further, this dosage will be optimized by reducing or increasing thedosage in response to continuing test results, particularly TCD andqEEG, showing reduction in frequency and/or severity of the patient'svasospasms. In most cases, just sufficient vasodilator will beadministered to achieve optimum reduction in vasospasms preferablymeasured as optimal TCD Mean Flow Velocity (MFV) at the respective stageof treatment. It will be recognized that these dosages are mainly farlower than the vasodilator dosages commonly employed to treat cardiacdisease and this is because the treatment of vasospasm needs much lowerdosage, and that vasospasm may even be induced by the vascular reactionto high dosages of vasodilator. Without being bound to any theory, itappears that the number of receptors increases during treatment, so thatsome patients are able to tolerate only lower dosages as treatmentcontinues. Thus, the “titration” of dosage from time to time on thebasis of test results is stressed in the present application.

[0039] Duration:

[0040] Because of the discovery that the vasospasms are not merelyacute, but are chronic, treatment duration will be prolonged in mostcases, extending over months and even years in some cases. Typicallytreatments will extend over about 5 to 250 weeks, more preferably 8 to100, and most preferably 12 to 60 weeks, though treatment duration willbe controlled by the patient's response as indicated by the continuingtesting.

[0041] Titration:

[0042] Frequent testing, as much as even several TCDs in a single dayduring initial treatment, will be used to titrate dosage so as to avoidoverdose (which can itself trigger vasospasms) as the patient'scondition improves.

[0043] Delivery Systems:

[0044] The average dosage on a typical patient will be in the range ofroughly one milligram per day. It is desirable to have delivery systems,sprays, ointments, creams, inhalers, and preferably patches of reduceddelivery as compared to the conventional systems now availablecommercially. Such reduced delivery systems are particularly desirablefor patients who tend to be too noncompliant, e.g. mentally impaired, tofollow reliably a treatment regimen of intermittently applying andremoving conventional patches to reduce dosage. Such vasodilatordelivery systems will preferably be marked (or packed) with theappropriate DRG and/or ICD 9th. codes and/or instructions for titratingand tapering their use, to facilitate their proper application.

[0045] 1. Utility of the Invention

[0046] This technique is useful in treating a variety of conditionsincluding closed head injury with vasospasm, attention deficit disorderwith vasospasm, migraine with inter-ictal evidence of vasospasm, syncopeor blackout spells of unknown aetiology with evidence of vasospasm,seizure with evidence of vasospasm, and dementia with evidence ofvasospasm, and post-concussion syndrome with evidence of vasospasm,migraine, post-concussion syndrome, sympathetic vasospasm associatedwith breast implants, and cerebral vasospasm. The invention embodies thediscovery that such vasospasms are a component symptom of many whiplashinjuries.

[0047] While less studied at present, the invention can be used todiagnose and treat the following other diseases which have now beenfound to frequently involve vasospasms: neurocognative disorders suchas, dyslexia, memory disturbances, depression, psychosis, reflexsympathetic dystrophy, mood disorders and sensory motor disorders;transient ischemic attack (TIA), pseudoseizure, hemibalism, and stroke;tremor, Parkinson's disease, torticollis, electrical shock trauma, aswell as any other disease in which vasospasm can be detected as acomponent of symptoms. Even cases of Benign Prostate Hypertrophy (BPH)can be treated with the vasodilators of the invention to relax thesmooth muscle of the sphincter (where the vasodilator relaxes the muscleeven where vasospasm is not a symptom) allowing better emptying of thebladder. Further clinical testing has also established the usefulness insome cases, of additional diseases which have now been foundunexpectedly to involve a substantial degree of vasospasm, comprising;vertigo, autism, depression, psychosis, transient global amnesia, memorydisabilities, balance disabilities, Tourette's Syndrome, Tinnnitis,Multiple Sclerosis and Multiple Sclerosis-like syndrome, hyperactivityand Attention Deficit Disorder, deficits resulting from strokes ofvarious causes, migraine, seizures, balance disorders, concussion,post-concussion syndrome sometimes including temporal mandible jointpain (TMJ) or facial pain, cerebral ischemia and other vascularcomponents discovered to be associated symptoms in some cases ofpsychiatric disorders such as chronic depression and some psychosis, aswell as vascular dysfunction from any cause such as kidney disease andperipheral vascular disease e.g. from diabetes, cholesterol, infectionor other cause. A basic factor is that neurological diseases are reallysymptom diagnoses for the most part. Thus depression is the diagnosisfor a specific type of behavioral abnormality, not the underlyingpathological or anatomical diagnosis. This is also true for stroke,multiple sclerosis, vertigo, balance disorders, and many other diseasesmay be directly caused by ischemia, or have a component of their problemcaused by ischemia, or have associated problems caused by vasospasmarising from their associated problems.

BRIEF DESCRIPTION OF THE DRAWINGS

[0048]FIG. 1 is a Transcranial Doppler (TCD) of MCA immediately prior totreatment by Nitroglycerine spray.

[0049]FIG. 2 is a TCD of MCA post Nitroglycerine spray obtained duringcontinuous monitoring.

[0050]FIG. 3 is a related raw EEG scan.

[0051]FIG. 4 is a brainmap showing a spatial distribution of alphafrequency mu rhythm.

[0052]FIG. 5 is a brainmap showing a spatial distribution of betafrequency mu rhythm

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES Whiplash, MS, Migraine

[0053] A clinical review and correlation among 38 whiplash patients, 19patients with MS-like syndrome, one with MS associated with breastimplants, as well as 5 migraine patients is presented. All patients havesimilar clinical complaints, EEG abnormalities, and cerebral vasospasmidentified on Transcranial Doppler testing. All have similar clinicalresponses to medication that resulted in clinical improvementparalleling the course of clinical resolution of the cerebral vasospasm.

[0054] Methodology:

[0055] All patients are evaluated with a complete history, physicalexam, and neurological exam by a Board Certified Neurologist. Allpatients have blood work consisting of a CBC with differential count andplatelets as well as an SMA-30 obtained. All whiplash related patientsunderwent a CT or MRI of the brain, EEG and qEEG, B-mode and spectralanalysis ultrasound of the subclavian, carotid, and vertebralcirculation, and Transcranial Doppler (TCD) examination of theintracranial circulation. In some situations, repetitive TranscranialDoppler examinations are performed on the same patient in the same day.Initially, these tests are performed by maintaining the probe on thepatient's head through the course of several hours, but later thetechnique involves using the same probe, patient position, technician,depth, and cranial window with serial but interrupted exams across thecourse of the day. In all cases, the highest spectral frequencies arerecorded, as well as repeat exams at the same depth and window as thebaseline pre-medication windows were obtained. Immediately prior toinitial TCD exams, a neurological exam is carried out. At the time ofinitiation of treatment for the cerebral vasospasm, at which timevasoactive medications are administered after the baseline TCD and neuroexam are obtained, repeat TCD exams are carried out and when medicationeffects on the intracranial circulation were identified, repeatneurological exams are obtained. In 5 patients, P300 are obtained priorto initiation of treatment and, again, several months later. The samemethodology is used in those patients referred for evaluation ofpossible MS-like syndrome as recognized in the recent global settlement.With these patients, triple evoked potentials, EEG and qEEG, and avascular evaluation as outlined above is carried out in all patients,and in 11 who decided to attempt treatment with vasoactive drugs, themethodology outlined above for initiation of as in the MVA-relatedpost-concussion syndrome are used. 10 of the 19 MS-like syndromepatients additionally had brain MRI tests performed. In 3 of the MS-likesyndrome patients, P300 tests are obtained and serial studies after 1-2months of treatment in all 3 were also obtained. The same methodologyare also used with respect to the patients with a history of migraine,although only two of these had MRI or head CT exams performed at time ofinitiation of treatment. All 5 had carried a diagnosis of migraineheadache for at least 10 years prior to evaluation.

[0056] All patients noted that these symptoms are intermittent inoccurrence, and at times some symptoms would coexist with othersymptoms, and at other times these symptoms would be dissociated eachfrom the other. All noted that the symptoms could be aggravated bystress. All patients had tried over the counter and prescriptionanti-inflammatories and muscle relaxants prior to and during the initialstages of evaluation without significant relief. All had been tried onFioricet or Fiorinal, Midrin (isometheptene mucate), and aspirin. 22 ofthe 38 patients had also been tried on calcium channel blockers, betablockers, Imitrex (sumatriptan succinate), and p.o. Toradol (ketorolactromethamine). 21 of the 38 used narcotics for pain control.Neurological exam on these patients are remarkable, during exacerbation,for lower extremity hyperreflexia, abnormal tandem gait, and abnormalRhomberg exam. All patients' examinations could be aggravated byinducing psychological stress in the patients or performing actions thatincreased their pain, as would occur by doing activities that wouldaggravate their neck discomfort. All patients had normal MRI or CTexamination of the brain EEG and qEEG exams are performed on each ofthese patients, with the following findings. All patients had a lowvoltage 5-20 microvolt polymorphic delta and theta pattern identified inthe frontal and temporal areas. Those who complained of ataxia andbalance disturbance had the same abnormalities identified in theoccipital lobe. All had a superimposed mu rhythm in the frontal andtemporal areas better identified on qEEG than on bipolar montages asthis rhythm appeared as a subharmonic superimposed over the posterioroccipital alpha rhythm on the bipolar montage. The qEEG, a 16 channelaverage referential montage, allowed improved definition of wave formanalysis and spatial distributions and confirmed the underlying EEGevaluations. TCD exams in all patients showed evidence of generalizedcerebral vasospasm as identified by Mean Flow Velocities (MFV) ofgreater than 0.1, more preferably 0.2 and most preferably 0.4meters/second in intracranial vessels (about 0.06, preferably 0.2 andmost preferably 0.3 meters/second for vertebrobasilar system) andprolonged diastolic flow component in which continued elevation ofdiastolic flow beyond end diastolic velocity occurs throughout theentire course of diastole. In all cases, the EEG and qEEG abnormalitiesmirrored the distribution of vascular abnormalities identified onTranscranial Doppler.

[0057] Results:

[0058] 38 patients referred with post-concussion syndrome after whiplashdue to fall, motor vehicle accident (MVA), or beating are evaluated. Oninitial evaluation, their clinical complaints included intermittentheadache, photophobia, visual blurring or transient scotomas,hyperacusis, word finding or word substitution problems, ataxia orbalance disturbance, memory and concentration lapses, and, in somecases, black out spells associated with syncope. A baseline bloodpressure, neurological exam and TCD are then obtained at the time ofinitiation of treatment, and treatment are initiated with nitroglycerinsublingual spray. Initially, continuous TCD monitoring was performed forout to two hours from administering the spray. Continuous monitoring wasperformed of that vessel previously identified to be in the most severespasm. Ongoing monitoring of blood pressure and pulse with an electronicmonitor was also performed. When pharmacological relaxation had peaked,repeat neurological exams are performed as well as patient's clinicalperspectives on their symptoms are sought.

[0059] All patients showed improvement in Mean Flow Velocities at 15minutes who are continuously monitored, and the peak degree ofrelaxation was seen at 1 hour with continued relaxation of theintracranial spasm identified out to two hours. At the time of peakrelaxation, approximately 1-2 hours out from administration of thenitroglycerin or other vasoactive drugs, a full TCD and neurologicalexam was carried out. No blood pressure changes, including orthostaticchanges, of significance are noted as defined as changes in systolic ordiastolic readings of 10 points or greater and changes in pulse of 10points or greater. Generally no changes in pulse or blood pressure arenoted beyond changes of less than 5 points in any of the readings.Continuous TCD monitoring was performed in 9 patients. Serial TCDmonitoring was performed in 25 patients, usually at 45-60 minutes postadministration. All patients showed clinical improvement, however 3patients did not show significant TCD improvement. These patients aresubsequently identified as unable to tolerate Nitroglycerine and arenitrite sensitive. In those patients who are continuing to be monitored,they redeveloped their subjective symptoms and objective examabnormalities as the vasospasm returned as documented on TCD.

[0060] The TCD exam became vital for individualizing treatment. It wasfound that the therapeutic window for Nitroglycerine changed over thefirst 3 months of treatment and patients frequently redeveloped theirsymptoms or developed migraine headaches. Here the TCD was vital formodifying treatment. In these patients, while on Nitroglycerine, arepeat TCD is obtained and then a therapeutic challenge is administeredby spray. Repeat TCD is obtained at 15 minute and 1 hour intervals.Those patients who had developed a Nitroglycerine-induced migraine ormigraine equivalent mirroring or superimposed on their original problemdeveloped worsening of the TCD at the 15 minute or the 1 hour interval.Those who required increases in their dose, showed improvement of MeanFlow Velocity on TCD. 1 patient who had previously failed Nitroglycerinespray or patch alone due to a nitrite sensitivity, and failed Nifedipinealone, is able to tolerate the two in a combined dose with virtualcomplete resolution of clinical symptoms as confirmed by history, exam,and TCD findings. With removal of the Nitroglycerine, while any degreeof abnormalities are still seen on TCD, applicant's patients' problemsrecur. However, with continuing treatment until Mean flow Velocity hasreturned to normal and is documented as normal during Nitroglycerinefree intervals during the day, the patients could then use theNitroglycerine spray or patch on a PRN basis for treatment of any of theabove mentioned complaints with great success rather than continuing torequire scheduled daily doses of medication.

[0061] While most patients eventually reached a peak daily dosage of 4-6hours in two to three divided doses on a nitroglycerin patch duringtreatment, dosage requirements varied from 10 minutes a day in twoadolescent girls, and one 30 year old male, up to a total of 24 hours aday for one 34 year old woman whose initial complaints prior to startingthe Nitrodur (nitroglycerin) patch included severe ataxia, confusion andintermittent syncope or episodes of hemiparesis in addition to thevisual blurring, headaches and concentration and memory changes seen inthe other patients.

[0062] Most patients are on this dose for 1-2 months, and then tapered.No patients who are able to tolerate Nitroglycerine treatment continuedto require narcotics, and only two of the above patients in this seriesremained on narcotics where 21 of the 38 who started treatment are onnarcotics for pain control. Of great significance is that 2 patientswith intermittent syncope also have episodic hemiplegic migraines. Theyshowed complete resolution of both of these problems shortly intotherapy. There are only 3 failures to treatment. 1 patient withpost-traumatic syncope of unknown aetiology who is nitrite sensitivecontinued with these episodes, and one such episode is brought on by 3minutes of a Nitrodur patch being applied. She eventually responds tomaintenance treatment with p.o. hydralazine in doses high enough totreat the vasospasm. The second patient is unable to tolerateNitroglycerine or short-acting nifedipine, which caused angina, but didrespond to Adalat, a long acting nifedipine preparation. The thirdcontinued on narcotics at low doses but unchanged from the dose shepresented on.

[0063] Applicant's patients range in age from 15-76, consisting of 12men and 26 women. In four patients with post-traumatic fibromyalgia andfibromyositis, the symptoms of fibromyalgia and fibromyositis completelyresolve while on Nitroglycerine. They are in the tapering phase, and thesymptoms are not recurring of these fibromyositic and fibromyalgicconditions. The P300 in the 5 patients evaluated also shows improvementduring the course of treatment. In 3 of these patients, this improvementis independently confirmed by the neuropsychologists treating thepatient. The other patients do not have ongoing neuropsychologicalfollow-up. FIGS. 1 and 2 represent examples of the baseline TCD whilepatient is symptomatic, and a follow-up TCD with resolution of patient'scomplaints after a Nitroglycerine sublingual spray. FIGS. 3, 4 & 5represent examples of raw EEG tracing obtained on an average referentialmontage and two accompanying qEEG epochs. The first brainmap, FIG. 4,shows examples of the distribution of the alpha frequency mu rhythm,frontally, temporally, and occipitally; and the second, FIG. 5, issimilar but shows that these mu rhythm frequencies are frequently in thebeta range. On these maps, the frontal lobe is to the top, and theoccipital lobe is inferior.

[0064] In 19 patients with MS-like syndrome and 1 with MS associatedwith breast implants, a similar pattern of complaints,Electro-encephalographic and TCD findings is seen. Our patients range inage from 23-61. The pattern of complaints is the sane as the whiplashpatients. Headache, concentration and memory disturbances, visualblurring, intermittent focusing abnormalities, balance disturbances,ataxia, photophobia, and hyperacusis are complained of in all patients.The severity of the complaints, however, tends to be less than that ofthe whiplash patients, however, their complaints of memory and cognitivedysfunction and mood swings tend to be considered by the patient to betheir most severe problem in all but the one case who is felt to haveMS. Of the 10 patients who had MRI's performed, 2 had a few scatteredUBO's consistent with small white matter infarcts, and one had largeplaques consistent with MS on MRI and brain biopsy. All patients hadfibromyalgia and fibromyositis.

[0065] All but one of the patients had MRI or surgical confirmation ofimplant rupture and in that one patient, it is clinically suspected dueto patient's symptoms, their progression, and length of time of implant(20 years). All patients had the same constellation of EEG and qEEGabnormalities, TCD abnormalities that paralleled the vasculardistribution of the EEG changes in a fashion identical to that seen inthe whiplash patients and that followed clinical distributions subservedby vasculature.

[0066] 11 patients decided to start treatment with vasoactivemedications. 10 started initially with IM Toradol, followed bymaintenance dosing of Toradol given by mouth is seen to give consistentimprovement clinically and with respect to the TCD. Unfortunately,gastritis developed in all cases and the patients are switched toNitroglycerine by spray and patch, and is joined by the 11th patient,who initiated treatment with Nitroglycerine. Again, using the methodoutlined for initiating treatment with the MVA patients, baseline bloodpressures, neuro exams, and TCD exams are performed with serialexaminations on the first day also carried out as previously discussed.Results are identical. All patients have dramatic clinical improvementin exam and clinical symptoms with resolution of vasospasm as documentedon TCD. All patients relapse as the initial dose of medication wears offas again documented by TCD. Although no patients are found to be nitritesensitive in this group of patients, the TCD again became invaluable inmonitoring and modifying dosage regimens. Interestingly, unlike thewhiplash related patients, most of whom are able to taper their use ofthe nitroglycerin use within three-four months of treatment initiationwithout requiring the use of other medications, none of the breastimplant cases have been able to dramatically reduce their need for themedication below a Nitrodur 0.1 mg patch for 4 hours a day. Again, thetherapeutic window for Nitroglycerine modified in these patients overtime, the TCD became again invaluable for individualizing the dosenecessary for treatment. In all patients who started the Nitroglycerinetreatment, the symptoms of fibromyalgia and fibromyositis resolved whileon therapy and returned if they stopped therapy.

[0067] Five patients had a history of intermittent migraine headache,with only one patient noticing intermittently a history of scintillatingscotoma as a prodrome to the headache. Later, after treatment had beeninitiated, all reported that they could start to recognize prodromesthat they previously did not consider as prodromes. These included mildbalance disturbance, feeling of a mildly clouded sensorium, or abruptsensation of severe fatigue of acute onset. All 5 patients are men, ages37-58. All showed evidence of vasospasm on TCD and the headache resolvedwith Nitroglycerine patches applied for 10 minutes to 1 hour. Follow-upTCD at the end of application of the patch are obtained in 3 patientswhich confirmed reduction of the vasospasm. At the time of symptomatictreatment, all patients had minimal lower extremity hyper-reflexia, anda minimally abnormal test on Rhomberg exam and tandem gait testing.These abnormalities all resolved with the nitroglycerin.

[0068] Discussion:

[0069] In applicant's practice, the association of cerebral vasospasm isconsistently found to be associated with a typical clinical complex.This complex includes complaints of balance and memory problems,intermittent visual blurring, scotomas, or difficulty focusing,intermittent photophobia, and/or hyperacusis, memory and concentrationlapses, word finding difficulties, dysaphasias; and, in more severecases, headache which sometimes progresses to hemiplegic migraine withdocumentable weakness, asymmetric reflexic changes or fanning of toes orfurther progression to headache associated syncope or syncope withtonic/clonic activity and post-ictal confusion. Neurological exam mostconsistently shows a positive Rhomberg exam, abnormal tandem gait, andin more severe cases showed fanning of toes or intermittent Babinski'sand reflex changes. The symptoms and neurological exam wax and wane inseverity of abnormalities. In whiplash patients, the exam worsens withpsychological stress or pain, and, in the breast implant patients,psychological stress would precipitate a worsening of the exam. Thepatients often appeared to be photophobic or would startle easily tosound. EEG and qEEG's, even those with syncope or syncope and secondary,observed, tonic/clonic activity, would be minimally abnormal. However,the pattern of EEG abnormalities, as well as the subjective complaintsand neurological exam findings, mirrored the vascular distribution ofthe abnormalities seen on TCD. Interestingly, this syndrome in thewhiplash patient and the breast implant patient has now been found toonly rarely develop immediately with the causative trauma, but insteadto develop over a time course of weeks to many months after theinitiating irritant.

[0070] In the early stages of treatment of these patients, applicantmonitors specific vessels continuously while giving patients test dosesof medication. applicant did this in order to more quickly evaluatewhich medications are most effective for each patient and toindividualize doses. It became clear that such extensive andtime-consuming studies are not necessary, as this condition of cerebralvasospasm in these patents is a generalized phenomenon to the cerebralcirculation. The problem is probably systematically generalized ascommon associated complaints during times of these previously mentionedcomplaints include prinz-metal type angina, intermittent coolness of theextremities to the touch, and menstrual cycle irregularities in somewomen. All of these symptoms, except for the menstrual cycleirregularities would be aggravated by stress and are improved bytreatment with the vasoactive drugs. BAER studies are initiallyperformed on many patients as part of the evaluation of the ataxia, butare not helpful as they frequently are abnormal if vertebral arteryspasm is seen on TCD. The BAER abnormalities resolved with resolution ofthe TCD spasms in those where applicant has had the opportunity torepeat the study. Significantly, though, those with abnormal BAER's atinstitution of therapy, had more severe reactions to the initial stagesof treatment with Nitroglycerine and reported more severe reactions thenthey had previously been treated with vaso-constrictive medications forheadache control. It has now been found that Nitroglycerine, in theearly stages of administration, can give transient severevasoconstrictive episodes, apparently due to a hypersensitivity reactionin which, during early administration of the drug, some individualsdevelop transient worsening of the vasospasm which may result clinicallyin migraine headache, seizure, or syncope. In some cases, such episodescan be mistaken for stroke.

[0071] Thus, great care must be used in administering this drug tosomeone in the midst of an exacerbation. In applicant's practice, thefirst dose of Nitroglycerine is always given under direct physicianobservation, immediately after obtaining a baseline TCD. This is done asthose patients with the most severe reactions to Nitroglycerinegenerally, but not invariably, had the most severe abnormalities on TCD,or are patients severely symptomatic for a long time, or are less thanthe age of 20. This transient supersensitivity may be witnessed on TCDbut did not occur with any of the other vasodilating medicationsapplicant has tried, specifically, p.o. clonidine, Dynacirc(isradipine), hydralazine, or long acting nifedipine. It, clinically,probably does occur in some patients after administration of the shortacting form of nifedipine but applicant has not personally witnessed theTCD reactions for this drug as applicant has with the other mentioneddrugs.

[0072] Multiple other vasoactive medications are tried on these patientsprior to attempting nitroglycerin. Those medications that causedvasoconstriction on the TCD, such as Stadol (butorphanol tartrate), DHE,and Imitrex, in every case worsened the patient's neurological exam andmentation but improved their headache. However, in applicant's patients,the more serious neurological events such as syncope, TIA, or seizures,are usually preceded by a headache. Due to applicant's concern thatheadaches may be a significant warning sign of impending seriousneurological events, the cerebral equivalent of angina, applicantattempted vasodilator to reduce the vasospasm. Those that resulted invascular dilatation, such as Toradol, Nitroglycerine, clonidine,hydralazine, Dynacirc, and long acting forms of nifedipine, all resultedin clinical and neurological exam improvement mirroring the TCD exam'simprovement. These medications also alleviated or treated the headache.All medications in this and generally reduce pulmonary capillary wedgepressure, which empirically defines a class of useful medications.

[0073] Common clinical symptoms of headache, intermittent visualabnormalities, ataxia or balance troubles in patients with usuallynormal brain CT or MRI scans but abnormal EEG and TCD findingssuggestive of cerebral vasospasm are presented. These patients are foundto have a clinical aggravation of their symptoms directly related to thedegree of vasospasm seen on TCD. Techniques which modified thisvasospasm could cause clinical improvement or worsening paralleling thedegree of severity seen on TCD. This application is not meant as a finalrecipe for the treatment of cerebral vasospasm on the outpatient basis,but instead is meant to provide basis for further study into themechanism of these findings in disparate conditions and possibilitiesfor treatment.

[0074] Applicant believes he is the first to identify vasospasm inpatients with the condition whiplash. Half of these patients are alsoidentified as having either closed head injury symptoms orpost-concussion syndrome symptoms. These patients haveneuropsychological testings which for the most part confirmed thefindings of closed head injury in the previously mentioned half of thegroup.

[0075] In treatment of patients with migraine headache, the presentstate of the art is to treat patients with migraine withvasoconstricting medications as opposed to vasodilation medications, andin fact the present state of treatment of these conditions with thevasodilating medications mentioned is considered that the vasodilatormay cause migraine headaches. Additionally, applicant has four patientswith attention deficit disorder and four patients with seizure, all withvasospasm and all of which have responded well seen from bothneuropsychological testing or seizure control with the use ofvasodilator as described herein. In summary, vasospasm has beendiscovered to be a clinically common and treatable entity.

[0076] In FDA attachments for medications in which migraine headache isidentified as a side effect, no indications for the previously mentionedtreatments are identified.

[0077] Additionally, good results are obtained in a number or patientspresenting with systemic disorders, including cases of fibromyalgia,cardiac disease and even gastric disorders, by testing and treatment toreduce or eliminate vasospasms according to the techniques describedabove. Still further study after the fling of the provisionalapplication shows good results in the treatment of additional diseaseswhich have now been found unexpectedly to involve a substantial degreeof vasospasm, comprising hyperactivity and Attention Deficit Disorder,deficits resulting from strokes of various causes, migraine, seizures,balance disorders, concussion, post-concussion syndrome sometimesincluding temporal mandible joint pain (TMJ) or facial pain, cerebralischemia and other vascular components discovered to be associatedsymptoms in some cases of psychiatric disorders such as chronicdepression and some psychosis. For brevity Appendix A (based on papersto be published) gives clinical details and the following Examplessummarize the clinical treatment and results.

[0078] While the diseases to which the new techniques have been foundapplicable seem to be disparate and unconnected, the modality bridgingall of them appears to be the relaxation of smooth muscle tissue bytreatment with low dosage of vasodilator and the titration of thisdosage over time to avoid overdosage as the patient's response to themedication changes. Thus, relaxation of smooth muscles underlying thevascular system alleviates vasospasm, the relaxation of spincter musclesalleviates BPH, and the relaxation of downstream arteries alleviates theeffect even of physical buildup of cholesterol.

EXAMPLE Attention Deficit Disorder

[0079] Attention Deficit Disorder has been found to affect more than 12percent of the school age population. This disorder has now been foundto continue into adulthood and many ADD adults with a mild condition hadproceeded through life undetected. Limited blood flow to the brain(cranial perfusion) has been postulated as a cause for this condition.Two adults, siblings, were evaluated and treated as taught herein,(aregimen was made up of a low dose Calcium Channel Blocker, and an ACEinhibitor along with low dose Nitroglycerine and a Clonidine patch), toincrease blood flow to the brain with results showing increased socialand emotional control of themselves and IQ improvement of approximately30 points. Also they improved in achievement motivation and specificgoals for their lives.

EXAMPLE Concussion or Post-Concussion Syndrome

[0080] It was discovered that most patients referred to a neurologist'soffice for brain injury or concussion do not have a brain injury.Rather, they have an injury to the control mechanism that controls bloodflow to the brain. This injury results in causing blood flow to thebrain to decrease. This drop off in blood flow accounts for all or muchof the clinical symptoms. It is reversible. Of 22 patients randomlyidentified by computer with presenting symptoms of brain injury and adiagnosis of concussion, one third had no brain injury, but only avascular disorder, and the other two thirds identified that asignificant portion, or all of their symptoms were alleviated with sheuse of common vasodilating medication. A further aspect was that 22 outof 22 patients referred for evaluation of closed head injury andconcussion complained, on careful questioning, of their symptomsbecoming worse as time went on. These symptoms that developed orworsened progressively were reversed with vasodilating medication.

EXAMPLE Psychosis Caused by Cerebral Ischemia

[0081] In this Example, a patient who has an acute psychotic break ispresented. The patient is identified as having a history of migrainesand then developing acute schizophrenia. She is hospitalized for anacute psychotic break. Due to difficulty in controlling the thoughtdisorder, the hospitalization is extended for 3 weeks. She is thenreleased and self-discontinued her medications. Out-patient evaluationof her reveals that the blood vessels leading into her brain are overlyconstricted, and she is placed on medication to dilate these bloodvessels. The patient's thought disorder processes, memory disturbancesand headaches completely resolve. This represents a new approach to thediagnosis and treatment of psychosis and underlying concerns.

EXAMPLE Reversing Stroke Using Common Vasodilators

[0082] In this Example, three patients with strokes improveddramatically in minutes to days after devastating strokes by using thenew therapy taught herein (e.g. Dynacirc 10 mg t.i.d. and repetitiveuses of Nitroglycerin.) The first patient developed a large stroke,which caused her to be able to walk only with assistance and a cane, andnot to be able to speak her thoughts. One month later, no major clinicalchanges had occurred. Within 45 minutes of instituting the presenttherapy, she can walk unassisted, speak normally and had only minimalweakness. By the next day, she can transfer from a dock to a boatunassisted. The second patient has been paralyzed for one year on hisleft side. Within one month, he has regained 80% of his strengththroughout most of his body. Within four months he can lift 300 poundswith his paralyzed leg and 120 pounds with his previously paralyzed arm.The third patient has severe weakness in his right arm and face for fourdays. Within one hour of starting treatment, he has regained most of theuse of his arm. Nitroglycerin and other medications all result inimprovement in the patient's headache, but also resulted in improvementof any other neurological abnormalities including balance disorders,gait disorders, hemiparesis, abnormal Babinski's and abnormal reflexes.

Modifications

[0083] Specific compositions, methods, or embodiments discussed areintended to be only illustrative of the invention disclosed by thisspecification. Variation on these compositions, methods, or embodimentsare readily apparent to a person of skill in the art based upon theteachings of this specification and are therefore intended to beincluded as part of the inventions disclosed herein.

[0084] For example, the vasodilators include many that are not namedhere, the tests for vasospasm are constantly improving and it will beevident that new tests for blood flow and others not named here will beuseful in the step of testing for vasospasm described in thisapplication and that the treatable diseases will expand as vasospasm isfound to be a component of additional diseases. Reference to documentsmade in the specification is intended to result in such patents orliterature being expressly incorporated herein by reference.

[0085] Appendix A

EXAMPLE

[0086] ADD Method:

[0087] Two individuals were referred for Career Evaluations by theirMother because they lacked ambition and success in work. They were a 27year old female and her 25 year old brother. They shared the samebiological parents, both professionals, and shared similar behaviorcharacteristics of:

[0088] Completing Junior College in 4+ years.

[0089] No record of full time employment for 4 months or longer.

[0090] Limited friendships.

[0091] No specific career plans.

[0092] Enthusiastic beginnings but poor or incomplete endings.

[0093] Underachievement in relation to ability.

[0094] Both were administered a battery of tests which measuredneuropsychological functioning and personality variables. Thesimilarities continued with both scoring in the superior range on anon-verbal abstract thinking intelligence test; average on theVocabulary subtest of the Wechsler Adult Intelligence Scale-Revised:average in fine motor coordination and organization.

[0095] Both scored low on achievement motivation, affiliation and theability to ask for assistance when they had no solution to a problems.They were high on aggression and needed control.

[0096] On referral for neurological evaluation, mild physical andsignificant objective testing abnormalities were found. Both patientsexhibited very mild balance difficulties only identified on carefulneurological testing. The patients had a mild tendency to sway whenstanding at attention with their eyes closed (abnormal Rhombergtesting). Both, further, had difficulty performing a Tandem Gait withcomplete ease. The physical exam was otherwise normal. An EEG andcomputerized EEG were performed and were abnormal. These tests showed afrontal and temporal spatially distributed alpha rhythm on an averagereferential montage. Transcranial Doppler ultrasound showed middlecerebral artery velocities of greater than 0.8 meters/second bilaterallyin the female, and 0.73 meters/second in the right MCA of the male, witha normal 0.26 meters/second in the left MCA. Interestingly, on aseparate day, the male was retested and found to have elevated MCA flowvelocities of 0.86 meters/second on the right, and 0.92 meters/second onthe left.

EXAMPLE ADD

[0097] Treatment:

[0098] Both individuals were treated with vasodilating medications for10 months and received psychotherapy and vocational counseling.Relaxation and hypnotherapy were also used to develop visualizationskills for both recall of successful social and work experiences and tovisualize successful outcomes of activities to do.

[0099] In serial testing, the male underwent TCD's on three separateoccasions on the same day. After repetitive applications ofNitroglycerin, the patient was re-examined and underwentself-assessment, and had repeat Transcranial Dopplers performed. As theright MCA mean flow velocity decreased from 0.86 meters/second to 0.79meters/second, to 0.72 meters/second, and the left MCA mean flowvelocity decreased from a baseline of 0.92 meters/second, to 0.84meters/second, to 0.79 meters/second, the patient's exam progressivelynormalized with eventual development of completely normal balancetesting. The patient also identified significant improvement inconcentration. By the end of the day, he identified that he could read,understand and retain news articles and magazine articles. He could alsofollow a television show throughout. He could do neither at thebeginning of the day. Observers also felt his comprehension hadsignificantly changed.

[0100] On the basis of the objective disorders of flow and the patient'sreported and observed improvement during the trial episode ofadministering medications to decrease the observed vasospasm, we startedthe brother on vasodilators. After the patient had been on medicationfor approximately 3 months, the sister's observations of significantimprovement in her brother's functioning resulted in her self-referringfor evaluation and treatment. We initially used Nitroglycerin and lateradded a variety of Angiotensin Converting Enzyme inhibitors, CalciumChannel blockers, and Clopidine until the regimen that the patient besttolerated was found. This regimen was made up of a low dose CalciumChannel Blocker, and an ACE inhibitor along with low dose Nitroglycerineand a Clonidine patch.

[0101] Over the next 6 months, both sibling's neurological examsnormalize. The Transcranial Doppler results showed marginal improvementfrom office visit to office visit. However, the patients have identifiedsignificant functional improvement which wears off in directrelationship to the vascular pharmacokinetics of the specific medicationused.

EXAMPLE ADD

[0102] Results:

[0103] Both the male and female subjects experienced social, emotional,physical and intellectual gains through these treatments. Their VerbalIQ scores increased from scores of 110 and 119 to 143 and 146respectively. On the Bender Gestalt Test they eliminated all errors andtheir drawings were better organized with improved fine-motorcoordination. Both have been planning a continuation of their collegeeducation with specific goals in mind. The young man had played tennisin high school and has maintained playing recreationally. He had notedspecific improvements in anticipating moves of his opponents and hadimproved his game significantly. This was also noted by his opponentsand fellow tennis teacher.

[0104] Their personalities changed significantly. The female became lessfearful and argumentative and was self assured. The male as stated “Ican relate to friends and I am not the last to get the joke. I am lessthe point of jokes and teasing.” These were significant personality andsocial changes for these individuals.

EXAMPLE ADD

[0105] Discussion of Possible Theory:

[0106] This study utilized siblings who had been considered OK in life,but themselves were frustrated and had self thoughts of failure. Basedon Career Neuropsychological testing, they were found to be Adult-ADD.After 10 months of treatment with vasodilating medications andpsychotherapy. they have improved their cognitive, social and emotionalfunctioning. Their gains have been significant and have stabilized.These have remained consistent for over 11 months and indicate apermanent solution.

[0107] From a neurological viewpoint, serial monitoring identified closerelationship between functional abilities and a degree of vasospasm orconstriction of the arteries. These patients' long term TCD's do notreflect major improvements in the resolution of the degree of spasm. Thelack of complete resolution of the vasospasm probably relates to, inthese two specific patients, their inability to tolerate even moderatelevels of vasodilators without developing symptomatic hypotension. Thesetwo patients share in common with all Applicant's patients referred foridiopathic Attention Deficit Disorder that we can seldom completelyresolve the vasospasm identified on ultrasound, but that any improvementin the arterial constriction parallels functional improvement. Patientswith secondary Attention Deficit Disorder-like syndromes, such as areseen after trauma, closed head injury, neck injury, Reflex SympatheticDystrophy, cerebrovascular accident, silicon implant disease and othertoxic vasculopathies, and so on, generally have profound vascularrelaxation with the commonly used vasodilators after approximately 6-10months of treatment. Nonetheless, our therapy in these two patients hasprobably been successful by causing vasodilation of the small arteriolesand other blood vessels in the brain. Such vasodilation would decreasethe ischemia of the brain tissue and improve performance. On a day whenserial testing was performed when repetitive vasodilation medicationdoses were used to decrease the vasospasm, the patient showedsignificant improvement. This argues that improved control of thevasospasm may be expected to cause further functional improvement.Equally, it is strongly recommended that psychological counseling andbiofeedback be utilized in the long term treatment of these patients, assuch treatment, by decreasing autonomic nervous tone, also enhancesvasodilation.

EXAMPLE ADD Literature

[0108] Learning disabilities (LD) and attention deficit hyperactivitydisorder (ADD) represent almost 25% of school age learning—conductproblems. Despite their prevalence, much confusion exists over thedifferentiation between LD and ADD. This confusion emanates from thefact that some individuals suffer from both disorders and school systemstend to group both disorders in the same classroom or diagnosticcategory. The major confusion results from the failure to appreciate theconsiderable progress that has been made in recent years in defining andclassifying each of these common neurocognitive and neurobehavioralproblems (Shaywitz, et.al., 1995, p.s50).

[0109] Hallowell & Ratey. 1994 have found that a large number of adultpatients viewed as depressed, anxious, obsessivecompulsive, personalitydisordered, dissociative or prone to substance abuse were ADD. Untilrecently mental health professionals have not paid much attention tothis disorder in adults, despite the fact that attentional disordershave major ramifications for intellectual cognitive and emotionalexperience. Miller, in a Wall Street Journal article in 1993. identifiedthe following as symptoms of ADD in adults:

[0110] A short attention span, especially for low-interest activities.

[0111] Enthusiastic beginnings but poor endings.

[0112] Low frustration tolerance.

[0113] Difficulty listening.

[0114] Argumentative.

[0115] Frequent job changes.

[0116] Underachievement in relation to ability.

[0117] Frequent and unpredictable mood swings.

[0118] Avoids group activities; a loner.

[0119] Spends excessive time at work because of inefficiency.

EXAMPLE ADD

[0120] Bibliography

[0121] Hallowell, Edward M. and Ratey, John J. Answers to Distraction,Pantheon Books, New York. 1994. p. 207-211.

[0122] Shaywitz, Bennett A., Fletcher, Jack M. and Shaywitz, Sally E.,“Defining and Classifying Learning Disabilities andAttention-Deficit/Hyperactivity Disorder.”, Journal of Child Neurology,Vol. 10 Supplement Number 1, January 1995.

[0123] Concussion or Post-Concussion Syndrome

[0124] Professional Abstract

[0125] This article represents the first discussion that concussion andpost-concussion symptoms as well as progressive deterioration after anaccident may be vascularly mediated. Progressive deterioration ofpatients, as well as patients complaining of concussion orpost-concussion syndrome or closed head injury, should include vascularultrasound screening of the brain.

[0126] This paper represents a complete evaluation of twenty-twopatients referred for evaluation of concussion and post-concussionsyndrome. All patients on referral from their primary treating physicianor psychologist also carried the diagnosis of concussion. All patientscomplained of progressive deterioration starting some time after anaccident.

[0127] Six of 22 patients had a loss of consciousness, 7 of 22 patientshad altered mental status at the time of the accident which clearedcompletely, and 9 of 22 patients had no concussion or mental symptoms,only spinal symptoms (2 of these 9 did have a headache). It is assumedthat one third of the patients did not have a brain injury at the timeof impact. An additional one third had complete resolution of allsymptoms after the trauma. However, by the time of presentation, all hadan abnormal neurological exam and symptoms of concussion, closed headinjury and post-concussion syndrome.

[0128] All patients were found to have vascular flow abnormalities bythe Transcranial Doppler (TCD) showing evidence of abnormal constrictionof the arteries intracranially. Other imaging modalities of thesepatients included CT and/or MRI scan in all patients, EEG andcomputerized EEG in all patients: SPECT scan and neuropsychologicaltesting were additionally added in many patients. The comparison ofthese various imaging and diagnostic modalities is made.

EXAMPLE Concussion or Post-Concussion Syndrome Comparative Analysis andEvaluation

[0129] Twenty-four patients having been computer coded as concussionsyndrome were chosen at random per data from the office computer; thepatients were seen in this office between Feb. 23, 1995 through January1996. Two of the patients were miscoded and were dropped from thisstudy. All patients were referred by their primary physician orpsychologist with the diagnosis of concussion. injuries of twentypatients were sustained by motor vehicle accidents and two patients'injuries were a result of falling. Each patient was given a neurologicalexamination by a board certified neurologist, Transcranial Dopplers,standard and quantitative EEGs, and most were given either/or MRIs or CTscans of the brain, neuropsychological testing, and three patients hadSPECT Scans of the brain.

EXAMPLE Concussion or Post-Concussion Syndrome Clinical PresentingSymptoms

[0130] Loss of consciousness varied with patients having very briefblack-outs of seconds to twenty-five minutes. Six patients had a loss ofconsciousness at the time of the accident with four patients unconsciousfor brief seconds, one patient for five minutes and one patient abouttwenty four hours. (Ref.Table IA. Period of Total Unconsciousness atScene of Accident with Other Related Symptoms)

[0131] There were seven patients that denied loss of consciousness buthad less severe altered mental status such as amnesia, mental confusion,dazed, dizziness, vertiginous and/or ataxia. (Ref.Table IB. AlteredMental Status With No Unconsciousness and Related Symptoms)

[0132] A third class of patients consisted of nine patients who had noaltered mental status but experienced a combination of a variety ofsymptoms such as neck and back pain (two of them also had a headache).One patient had no symptoms at all at the time of the accident butdeveloped severe back pain later at night following the accident. (Ref.Table IC. Physical Symptoms With No Altered Mental Status.)

[0133] Table IA Period of Unconsciousness at Scene of Accident and OtherRelated Symptoms #of Patients Period of Total Unconsciousness & RelatedSymptoms

[0134] 4 Brief loss of consciousness with neck and back pain of secondsto less than 5 minutes

[0135] 1 Loss of consciousness for 5 minutes, dazed, confused with neckand back pain

[0136] 1 Loss of consciousness for about 24 hours & awoke with neck andback pain

[0137] Table IB. Altered Mental Status with Related Symptoms but NoTotal Unconsciousness

[0138] 3 Immediate severe headaches, confusion, neck and back pain

[0139] 1 Neck and back pain, vertiginous and nausea

[0140] 3 Amnesic for accident, confusion, back and neck pain

[0141] Table IC: Physical Symptoms with No Alter Mental Status

[0142] 2 TMJ and neck pain

[0143] 1 Neck pain only

[0144] 3 Neck and back pain

[0145] 2 Headaches and severe neck pain

[0146] 1 No symptoms at all at time of accident but later that nightdeveloped back pain.

EXAMPLE Concussion or Post-Concussion Syndrome Additional PhysicalSymptoms

[0147] Temporomandibular Joint Injury

[0148] An associated finding in this study was TMJ and facial pain. Ofthe twenty-two patients studied fifteen patients had pain in thetemporal mandibular joints with ten of the patients diagnosed withhaving TMJ and five patients with mild symptoms of popping of TMJ wasconsidered to be clinically insignificant. Onset of symptoms varied fromimmediate discomfort to four months post the accident. Some of patientsthat were later diagnosed as having TMJ related that in the beginning,they had so much head and facial pain that they were not able todetermine where the pain was coming from until they have had a chancefor some of the injuries to heal (Ref. Table ID. Time of Onset of TMJSymptoms Following Accident)

[0149] Table 1D. Time of Onset of TMJ Symptoms Following Accident

[0150] 5 patients don't know when pain was localized to TMJ

[0151] 2 patients had immediate pain in TMJ

[0152] 1 patient had pain about two hours later

[0153] 3 patients had pain not immediately but within twenty-four hoursof trauma

[0154] 1 patient with previous treated TMJ became worse withintwenty-four hours following new injury

[0155] 3 patients pain was localized to TMJ 2 months post accident

EXAMPLE Concussion or Post-Concussion Syndrome Thoracic Outlet Syndrome

[0156] A common associated complaint was symptoms of upper extremityintermittent paresthesias consistent with Thoracic Outlet Syndrome. Onlyrarely debilitating, and not complained of by the patient unless checkedfor during a Review of Systems of 22 patients. (Ref. Table 1E.).

[0157] Table 1E.

[0158] 19 had Thoracic Outlet Syndrome.

[0159] 3 had no symptoms of Thoracic Outlet Syndrome.

[0160] Interval Between Date of Injury and Presentation:

[0161] Time lapse between the date of injury and the patient's initialoffice visit varied from two weeks post accident to years. (Ref. TableII, Time Lapse from Date of Accident & Initial Office Visit)

[0162] Table II, Time Lapse from Date of Accident & Initial Office Visit# of Patients Lapse time injury and initial office visit

[0163] 1 11 days post accident

[0164] 3 1 month

[0165] 2 2 months

[0166] 4 3 months

[0167] 1 4 months

[0168] 1 5 months

[0169] 3 6 months

[0170] 1 7 months

[0171] 1 8 months

[0172] 1 14 months

[0173] 1 16 months

[0174] 2 3 years 1 25 years

[0175] Previous History of Head Injury:

[0176] An interesting finding during this survey was that 50% of thepatients have had at least one previous accident.(Ref. Table III.Previous History of Head injury. Two of these patients had loss ofconsciousness, one for less than 24 hours and the other patient, with aGlasgow Score of 4, was unconscious for three months. (Ref. Table III,Previous History of Head Injury)

[0177] Table III. Previous History of Head Injury

[0178] 13 patients had never had a previous accident

[0179] 4 have had 1 previous accident

[0180] 2 have had 2 previous accidents

[0181] 3 have had 3 previous accidents

EXAMPLE Concussion or Post-Concussion Syndrome Clinical PresentingSymptoms Summary

[0182] All patients developed delayed and progressive symptoms whichconsisted of as neck and shoulder spasms migraine headaches, memory andconcentration problems, easy distractibility in an attentiondeficit-like disorder, and most complained of intermittent upper and/orlower extremity paresthesias due to associated spinal injuries. Mostpatients complained of intermittent balance problems of varying, usuallymind severity, tinnitus and/or visual burring were also frequentcomplaints.

EXAMPLE Concussion or Post-Concussion Syndrome

[0183] Testing Results:

[0184] The patients were evaluated using multi-modality neuro-diagnosticand imaging techniques. vaso A discussion of MRI, SPECT scan results,neuropsychological testing, Transcranial Doppler, EEG and QEEG follows.All modalities proved to be of value.

[0185] EEG and QEEG Results:

[0186] With respect to EEG's, correlation of the abnormalities seen inthe standard and quantitative EEGs are very close in some cases, but inother cases abnormalities are seen in the standard EEG that are not seenin the qualitative EEGs and vice versa. The most common feature observedin the standard EEG being an alpha-like rhythm occurring bilaterally inthe frontal and temporal areas that was disassociated from the posterioralpha band seen only on an average referential montage. The quantitativeEEG's most common finding was an underlying-slowing in the theta and/ordelta frequency range located bilaterally in the frontal and temporalareas and at times appearing in the posterior head regions.Epileptogenic spike discharges obvious in both standard, andquantitative but not in the averaged EEG. However, the QEEG aided inlocalization of the discharges with further analysis. (Ref. Table IV,Comparison of Findings of Standard and Qualitative EEGs)

[0187] Table IV. Comparison of Findings of Standard and QuantitativeEEGs:

[0188] A. Summation of Standard and Quantitative EEG Findings:

[0189] 18 Patients had abnormal standard and quantitative EEGs

[0190] 4 Patients had normal standard and quantitative EEGs

[0191] 2 Patients had epileptogenic spike discharges obvious in bothstandard and quantitative EEGs but not in the average EEG.

EXAMPLE Psychosis Caused by Cerebral Ischemia

[0192] Professional Abstract;

[0193] A patient with a schizophrenic reaction after a long history ofmigraines is presented. The patient was hospitalized for an acutepsychotic break. Due to difficulty with regulating the thought disorder,the hospitalization was extended to 3 weeks. On discharge, the patientself-discontinued her medications with a return of headaches and thoughtdisorders. Evaluation of her including EEG and vascular evaluation ofthe brain showed abnormalities. The patient was placed on medication totreat the vascular constrictive disorder and the patient's thoughtprocesses returned to normal and the patient became headache free.

[0194] Case Study

[0195] The patient presented with a long history of migraine headacheswhich had progressed over the year prior to development of herschizophrenic break. The headaches would become daily. The patient notedat times, due to the headaches, she would have intermittent degrees ofconfusion, disorientation or memory disturbances. She had no history ofseizures. Two months prior to presentation she became increasinglydistressed about personal family issues with aggravation of theheadaches. She treated herself with over-the-counter medications andthen became concerned that her husband might be leaving her. She wentdown to meet him at his place at work, but became confused about how toenter the building, and decided he was probably trying to leave thestate. She stole a truck, drove along the road she thought would lead tohim. She was followed by police who identified her as havingdisorientated thought processes. She was hospitalized for psychologicalevaluation, was found to have a reactive psychosis and schizophreniformdisorder.

[0196] The patient continued to have hallucinations and delusions, wasplaced on Haldol (Haloperidol) from which she did not respond. Headachewas not a significant complaint in the hospital. She was eventuallyplaced on a combination of Navanne (Thiothixene) and Ativan (Lorazepam).She improved significantly. Blood work including thyroid studies werenormal. The patient was released and continued to have severe headaches,concentration problems and memory problems. She felt these problems wereaggravated by activity. Her neurological examination was normal A CTscan of the brain was obtained which was normal. An EEG and a QEEGshowed intermittent left temporal spike discharges, as well as bifrontaltemporal slowing activity in the 5 mv range in the delta and thetapatterns. A frontal alpha frequency band was also identified on anaverage referential montage as well as the computerized EEG.Transcranial doppler Artery showed evidence of mean flow velocities inthe MCAs bilaterally of 0.65 to 0.75 meters per second, and the basilarartery of 0.7 meters per second.

[0197] The patient was placed on Inderal (Propranolol) as well asDepakote (Sodium Valproate) without change in her EEG and continued flowabnormalities on Transcranial Doppler Artery. The patient was thenplaced on Nitroglycerin with complete resolution of her daily headachesand improvement in her middle cerebral artery flows to the normal range.

[0198] While taking Nitroglycerin medication, the TCDs continued toimprove with MCAs approaching 0.37 meters per second to 0.5 meters persecond. The patient's headaches completely resolved as did memorydisturbances, concentration problems and emotional lability.

[0199] Discussion

[0200] The patient has a long history of migraine and develolpedmigraine and/or stress-induced schizophrenic reaction. She had poorresponse to Haldol (Haloperidol), but good response to Navane(Thiothixene). On presentation to the neurologist's office, the patientwas off Navanne and evidence of vasospasm and evidence consistent withcerebral ischemia as well as the spike discharge was identified on EEG.The patient did not respond to standard antimigraine medication orseizure medication. The patient responded promptly to low-doseNitroglycerin for control and management for migraines with no recurrentepisodes of thought process disorders, memory disorders ordisorientation when taking medication.

[0201] This suggests that some patients with vasospasm andvasoconstriction with secondary ischemia of the brain may developneurocognitive changes including psychosis. Applicant has had severalother patients with diagnoses of chronic depression or of steroidinduced psychosis, in these cases headache was not a complaint, who hadsimilar vasospasm identified on Transcranial Doppler and similar EEGchanges as this patient. They also responded with clearing of theirpsychiatric disorders with vasodilators. It is thus our recommendationthat, in the evaluation of the psychotic or psychiatric patient,evaluation for vasospasm and cerebral ischemia should be performed andtreatment instituted empirically to reverse any abnormalities found, asthe psychiatric disturbance may have a vascular component.

[0202] Migraine Forum (Whip-Lash/Breast Implants/Migraine)

[0203] Applicant has a baseline practice consisting of mainlypost-traumatic, closed-head injuries and post-traumatic migrainedisorders of which many have attention deficit disorders (ADD). However,several years ago Applicant had a large number of patients who presentedwith ADD of which the origin of their problems was associated withsilicon breast implants (silicon toxicity). What became evident inevaluating of these patients was that the neuropsychological tests,computerized EEG and Transcranial Artery Doppler results wereessentially identical. Another common characteristic in these patientswas the waxing and waning nature of at least some of their complaints.Those patients with Attention Deficit Disorder both post-traumatic andin particularly those patients with silicon breast implant disease withMS-like syndrome would have normal neurological examination one day andon another day the exam would be normal. This finding substantiated thepatients' complaints of waxing and waning of symptoms and seemed to berelated to the degree of physiological or psychological stress thepatient experienced when being interviewed or tested. The degree ofabnormality of neurological exams would extend to the point of normal orabnormal Romberg and Tandem Gaits, reflex examinations and Babinskiexaminations in the same patient. Evoked potential test results variedfrom normal to abnormal on different days and the testing was performedby the same examiners.

[0204] In this same time frame, a series of new medications weredeveloped to treat migraine headaches. As headache was a major complaintof many of Applicant's patients, we tried these medications outincluding Imitrex (Sumatriptan), IM Toradol (Ketoralac) and othermedications under direct monitoring. As Applicant's patients tend to beintractable, it was not expected that any of these medications wouldhave dramatic results. Rather, it was expected that one or another setof medications might help point the way into using specific classes ofmedications or approaches. Accordingly, each of these patients.equivalent of a large number of patients, were monitored continuouslyacross the day. The patients would come in and be hooked up with EEG'sor Brain Stem Auditory Evoked Responses, or VEP's, or TranscranialDopplers, and across the day would have many of the differentshort-acting medications tried on them to see which would work and whichmonitoring tool would be most effective in identifying the improvement.

[0205] With respect to the different monitoring tools, some were morehelpful than others. It was found that the EEG was not very sensitive.The Brain Stem Auditory Evoked Response and other evoked potential testswere very insensitive tools for monitoring, because of the length oftime required to perform the test after short-acting medications weregiven in IM or sublingual or nasal spray administration route. TheTranscranial Doppler consistently appeared to give the best indicationas to which medications would work. If an ultrasound showed improvement,the patient invariably also reported improvement in their clinicalsymptoms. These symptoms included not only headache, but also sensationsof confusion, balance disorder, abnormal Romberg or Tandem Gait of otherneurological abnormalities. If the medications showed evidence ofincreasing vasoconstriction on the doppler, the patients who had aheadache, frequently reported improvement in the headache, but aworsening of their confusional state or a worsening of otherneurological symptoms. Those patients were identified as havingimprovement on ultrasound with doppler also showed resolution of theirheadache, but did not show the deterioration in their neurologicaleffects. This was completely unexpected. The general approach towardsmigraine and headache has always been that the headache represents avasodilation and frequently a hyperperfusion state. The aura, of course,represents a vasoconstrictive phase. What our results seemed to suggestwas that the doppler, which looks at essentially the area of bloodvessels around the base of the brain, was showing vasoconstriction.Vasoconstrictive medicines would relieve the headache presumably througha similar mechanism, as a vasoconstrictive medication probably relievedcoronary artery disease. It would relieve it by decreasing thevasodilation that occurs downstream from the area we are able todirectly insonate.

[0206] Unfortunately, if cerebral artery disease is anything likecoronary artery disease, that downstream dilation represents an attemptby the body to compensate and maintain perfusion to thus becomingischemic.

[0207] In Applicant's patient population all medications which resultedin vasoconstriction. relieved the headache, but caused neurologicaldeterioration. As the medication wore off, as documented by thepatient's clinical symptoms, sonography data, the patient's neurologicalabnormalities improved. Similarly, those medicines which resulted indirect vasodilation such as Hydralazine (Apresoline), Nitroglycerin andother medications all resulted in improvement in the patient's headache,but also resulted in improvement of any other neurological abnormalitiesincluding balance disorders, gait disorders, hemiparesis, abnormalBabinski's and abnormal reflexes.

[0208] Observations Noted Concerning Transcranial Dopplers

[0209] A special word about Transcranial Doppler needs to be made. Wefound that morphology of a Transcranial Doppler Artery Ultrasound is asimportant as mean flow velocities. In our patients, as they became morenormal, and as their fixed deficits and europsychological abnormalitiesresolved etc., the morphology of the wave form would be similar to thatof an internal carotid artery tracing. We did not find that there wouldbe elevation of flow readings throughout diastole, as is more commonlypublished. It is important to identity that the original normative dataobtained in 1979, used for “Normals” patients with post-traumaticmigraine disorders, “psychogenic seizures”, and the interictal migrainephase may not be appropriate. It is important to note that other labswhich have done less extensive studies of normal versus non-normal, mayhave unknowingly used many patients with a history of migraines orwhiplash headaches. Some have not identified the close relationshipbetween degree of vasospasm and clinical abnormalities. This may be dueto less lengthy monitoring or evaluations being carried out by thoselabs in comparison to our own. Equally, the trend clinical correlationis a general one. Remembering hemodynamics, it is important to note thatif the blood vessel is constricted, patients do have a limited abilityto compensate for the effects of that vasoconstriction by dilatingdistally to the constricted area.

[0210] Patients will not be abnormal clinically during the early stagesof constriction of an artery. It is only once the downstream area is nolonger able to dilate to a degree enough to maintain a significantpressure gradient across the vasoconstricted area that the patient willdevelop symptoms. It is important to continue to monitor and treat thesepatients until the sonographic studies return to normal and beyond.Realizing that blood vessels constrict across the day in response tosympathetic nervous system variability, internal steroid release,physiological and psychological stress, including the physiologicalstress of photic stimulation, driving etc., and thus to obtain anultrasound at one moment, must be correlated with the patient's clinicalsymptoms and any complaints of variability across the day.

[0211] We also found that over time, chronic, untreated patient studiesfrequently falsely appear to normalize with a dropping of mean flowvelocities. This occurs as the body develops compensating mechanisms torelieve the ischemia. Thus morphology becomes extremely important inidentifying those who have ongoing vasoconstrictive disorderintracranially. The development of a pattern a time goes on is to have ablunted upstroke in the systolic portion of the ultrasound, but with anoverall mean flow velocity of less than 0.6 meters per second. Thatblunting, which is also seen in disseminated vascular disease from anycause, is highly suspicious for severe vasospastic disorder. Acomputerized EEG or standard EEG consistent with brain dysfunction orischemia, and/or neuropsych testing consistent with variability ofcognitive injury (especially with fluctuating cognitive deficits acrossseveral hours or days of testing) with ischemia is often helpfulcorroborating study. These are patients who should not be treatedinitially with Nitroglycerin or other potent medications, but shouldfirst have other medications which are direct vasodilators instituted atlow doses and slowly advanced as the patient is able to tolerate it.This institution with alternative vasodilators, tends to decrease theincidence of a potentially dangerous nitric oxide sensitivity reaction.

[0212] With respect to Nitroglycerin, what we have seen is several timecourses of the effect of Nitroglycerin. The first is an acute effectwhich lasts between 15 and 45 minutes. The method of administrationbeing a patch, pill or sublingual spray determines the rapidity ofabsorption and distribution. It seems to have a lingering effect forapproximately 2 to 3 hours. Nitroglycerin then gets converted into avariety of subsidiary byproducts, all with some vasodilating properties.Each of these medications themselves can accumulate in patients to toxicdoses, and can cause a reactive cerebral vasoconstriction. Thus, it iseasier to maintain patients on intermittent low dose Nitroglycerinapplications, then chronic applications of medication, as the clinicaldata and clinical response to the vasodilator challenge becomesconfused. With respect to Nitric Oxide sensitivity, those patients inApplicant's clinical practice who have not been premedicated with a betablocker, an alpha blocker or a direct vasodilator such as a calciumchannel blocker or an ACE inhibitor, who are given their first dose ofNitric Oxide and developed acute erythema of the nose or face, arehaving a reactive vasoconstriction and distal vasodilation occurring atthe same time. Those patients on Transcranial Doppler Artery Ultrasoundwill have acute spasm of the arteries and active constrictions anddilations may frequently be seen. Those patients may have a seizure or astroke or a blackout spell. This problem can be immediately reversedwith IM Toradol (ketoralac). Toradol in 90 to 120 mg IM doses causesacute vasodilation on ultrasound in most patients. In lower doses, theTranscranial Doppler Artery ultrasounds generally do not showsignificant changes, but the patient reports a symptomatic improvement.For most patients, standard doses of nitrates in any form will aggravatethe vasospasm.

[0213] IV Toradol (Ketorolac) in 30 to 60 mg doses does not cause anyimprovement on Transcranial Doppler Artery Ultrasound, and patientsgenerally report a sensation of vertebrogenic syndrome with increasespaciness, confusion, worsening headache and worsening spasm. AlthoughApplicant has not identified this directly, their clinical course isthat of a development of a vasoconstricted vertebral or basilar arterysyndrome. This probably relates to a carrier drug in the I.V. Toradolsolution, as giving the Toradol intramuscularly (I.M.) or in thealternative oral form after oral or I.M. loading gives the expectedvasodilation. Without a change in formulation, Applicant would notrecommend the I.V. use of Toradol to reverse acute and life threateningvasospasm or stroke. Multiple medications over the last several yearshave now been tried for the vasodilators. Each of these classes andresults will be discussed in their specific following paragraphs.

[0214] With respect to betablockers, Inderal (Propranolol), Tenormin(Atenolol), Normodyne (Labetolol), Lopressor (Metoprolol) have all beentried. None of these have been significantly effective at vasodilation.However, when using vasodilators, patients will frequently notice waxingand waning of their effectiveness. This is especially noticeable inpatients who are beginning to be tapered off their medications due togood responses, and thus cannot tolerate higher doses of vasodilatorswithout developing symptomatic lethargy, hypotension, etc. from themedications. In these patients Beta blockers have been extremelyeffective in smoothing out the sympathetic nervous system excitabilityand variability that may be seen. In Applicant's patient population,Inderal (Propranolol) has been most effective. The other medicationshave not been effective, although probably are useful in blunting anyacute response to Nitroglycerin administration from a hypersensitiveNitric Oxide response, if the patient is prone to such a response. Alphablockers have been tried Clonidine has been extremely effective. Hytrin(Terazosin), Ismelin (Guanethidine). Minipress (Prazosin), have been alltried, with less successful results. Cardura (Doxazosin) is still beingtried, but initial results are just now coming available. Dibenzyline(Phenoxybenzamine) has also been tried, and appears to be relativelymild, similar in action on the vasospasm as Hytrin (Terazosin).Angiotensin Converting Enzyme Inhibitors (ACE) inhibitors have beentried including Accupril (Quinapril), Altace (Ramipril),Capoten(Captopril), Lotensin (Benazepril), Monopril (Fosinopril),Prinivil (Lisinopril), Zestril (Lisinopril timed released), Univasc(Moexipril), Vasotec (Elalapril), Cozaar (Losartan). Accupril(Quinapril) has consistently been the most effective.

[0215] With use of Accupril (Quinapril) and concomitant administrationof low dose Nitroglycerin, {fraction (1/10)}th inch once a day toseveral times a day, most patients may be eventually weaned from the useof oral medications, although Applicant do tend to maintain them on lowdose Nitroglycerin in perpetuity, as the inciting cause of the vasospasmusually remains and usually causes redevelopment of symptoms. However,these symptoms and radiological as well as symptomatic vasospasm may becontrolled with low dose medication if Accupril (Quinapril) is usedinitially. The timed release medications such as Zestril (Lisinopril)are extremely effective in part due to increased patient compliance.Although Applicant personally finds these two aforementioned medicationsthe most helpful, Capoten (Captoptil), Lotensin (Benzepril), Prinivil(Lisinopril) are close second tier medications. The other ACE inhibitorstend to be effective, but a third tier alternative drug. However, as apatient becomes intolerant to the stronger ACE inhibitors, these secondand third tier drugs may be very helpful in preventing and controllingthe vasospasm without developing intolerance to the medication.Similarly, in less severe cases, these are excellent first line drugs.Calcium channel blockers have been tried. In the most severe cases,Dynacirc (Isradapine) has been extremely effective. Adult (Nifedipine)in standard doses and timed release dosages has been helpful but as asecond line drug. Careen (Nicardipine), Nimotop (Nimodopine), Cardizem(Diltiazem), Norvasc (Amlodipine) have been less effective in relievingthe vasospasm or in allowing a degree of vascular relaxation sufficientto allow the patient to taper from the medication over time. Sular(Nisoldipine) and Plendil (Felodipine) appears to be slightly milderthan Dynacirc (Isradapine) and has been effective in those that couldnot tolerate Dynacirc. Verapamil in its many manifestations is onlyrarely used, due to its minimal direct effect on vasodilating thevasculature as documented by Transcranial Doppler or in its ability toaffect the outcome of these disorders. Vascor (Bepridil) is just nowbeing tried on some patients. Of course, the general comments concerningACE inhibitors also apply to these medicines. Applicant's first linemedications may be too strong for the other physicians' patientpopulations if those practices don't tend to attract as severelyimpaired individuals. Thus, the second and third tier medications may bebetter tolerated in less severely affected people, and similarly, aspatients are able to taper from medications, they may taper into moremild medications from the same classes as previously were shown to besuccessful. Other Vasodilators that have not been previously discussedhave also been tried. Hydralazine is effective, but tends to causesignificant blood pressure changes in these patients.

[0216] Interestingly through, Hydralazine tends to improve themorphology of the diastolic flow component dramatically, which, in viewof Hydralazine's effect on arterioles, bolsters the perspective that thediastolic phase of the Transcranial Doppler is a good indicator ofdownstream runoff. Flolan (Epoprostenol) has not yet been tried, nor hasIV Papaverine or Inocor (Amrinone). Reserpine has been extensively used.It can be very effective. It's initial effect is parasympathomimetic. Alater effect is sympatholytic. Its role is that it may be veryeffectively used as an adjunctive drug especially when patients havedifficulty tolerating stronger vasodilators. The dose which initially ismost effective of Reserpine frequently needs to be decreaseddramatically (generally 50%) approximately 6 weeks into therapy as thesympatholytic activities start to become significant. Antipsychoticagents have also been used. Several of Applicant's patients whoApplicant will be reporting on later, were psychotic, and responded wellto these medications and had significant vasospasm identified onultrasound which improved after the administration of medication. Of theantipsychotic. Mellaril (Thioridizine) has not been effective. ThorazineChlorpromazine) has been moderately effected Navane (Thiothixene) hasbeen extremely effective, and Respiradol (Respiradone) has generallyimproved the patient's symptoms, but had no significant improvement onultrasound. It has been less well-tolerated in comparison with Thorazineand Navane, interestingly enough, most of the patients who were placedon Navane, did not continue to require Navane two to three months afterstarting the medication, and were able to be weaned from that and hadbetter response to their other vasodilators. In general, Navane was usedas a first line drug in patients who had severe elevations ofTranscranial Doppler Artery mean flow velocities greater than 1.3, andwe would generally expect 50% improvement in the Transcranial DopplerArtery Ultrasound within a half hour of administering Navane by liquidsolution. The solution was made by stirring 2 mg of Navane in 4 ouncesof water then administered orally. The patients were usually afterwardsplaced on vasodilators such as ace inhibitors and calcium channelblockers.

[0217] Problems

[0218] The approach used in Applicant's clinical practice of over 2,000patients, is the approach of using vasodilators to treat migraineheadache, to cause improvement in closed head injury symptoms, and totreat vasospasm from any cause. This has also been effective inAttention Deficit Disorder (ADD) and multiple other disorders withcerebral ischemia or vasospasm as a component. A partial list of thesedisorders, include Vascular Seizures, Vertigo, Tinnitis, PostSubarachnoid Hemmorhage Vasospasm secondary to both aneurysm rupture ortrauma, Stroke, reversal of a chronic stroke penumbra, autism,depression, Post-Traumatic Stress Syndrome, autism, dyslexia, visualdisturbances and blindness, Autism, Tourette's Syndrome, Tics, Tremors.Ataxia and multiple other neurocognitive, neuropsychiatric, andneurological disorders that have vasospasm and ischemia as a commonaetiology, systemic disorders with diffuse vascular involvement, i.e.some types of Fibromyalgia and Prinz Metal Angina may also be treatedwith this approach. The approach to treatment and results areessentially identical in these cases, with minor variations.

[0219] However, 10% of patients placed on antihypertensives will developperipheral hypotension before the vasospasm is successfully treated. Inthose patients, Navane (Thiothixene) and other antipsychotics of thatgroup, have been found to be an extremely effective central vasodilatorwithout causing peripheral blood pressure changes. These patients may dowell on low dose Angiotensin Converting Enzyme Inhibitors. CalciumChannel Blockers. Alpha blockers and/or Nitrates with the use of Navane(Thiothixene) and the other anti=A9psychotics of that group and haveexcellent resolution of vasospasm.

[0220] 02747E14E5C

EXAMPLE Whip-Lash/Breast Implants/Migraine

[0221] Applicant has a baseline practice consisting of mainlypost-traumatic, closed-head injuries and post-traumatic migrainedisorders of which many have attention deficit disorders, (ADD).However, several years ago Applicant had a large number of patients whopresented with ADD of which the origin of their problems was associatedwith silicon breast implants (silicon toxicity). What became evident inevaluating of these patients was that the neuropsychological tests,computerized EEG and Transcranial Artery Doppler results wereessentially identical. Another common characteristic in these patientswas the waxing and waning nature of at least some of their complaints.Those patients with Attention Deficit Disorder both post-traumatic andin particularly those patients with silicon breast implant disease withMS-like syndrome would have normal neurological examination one day andon another day the exam would be normal. This finding substantiated thepatients' complaints of waxing and waning of symptoms and seemed to berelated to the degree of physiological or psychological stress thepatient experienced when being interviewed or tested.

[0222] The degree of abnormality of neurological exams would extend tothe point of normal or abnormal Romberg and Tandem Gaits, reflexexaminations and Babinski examinations in the same patient. Evokedpotential test results varied from normal to abnormal on different daysand the testing was performed by the same examiners.

[0223] In this same time frames a series of new medications weredeveloped to treat migraine headaches. As headache was a major complaintof many of these patients, Applicant tried these medications outincluding Imitrex (Sumatriptan), IM Toradol (Ketoralac) and othermedications under direct monitoring. As these patients tend to beintractable, it was not expected that any of these medications wouldhave dramatic results. Rather, it was expected that one or another setof medications might help point the way into using specific classes ofmedications or approaches. Accordingly, each of these patients,equivalent of a large number of patients, is monitored continuouslyacross the day. The patients are hooked up with EEG's or Brain StemAuditory Evoked Responses, or VEP's, or Transcranial Dopplers, andacross the day would have many of the different short-acting medicationstried on them to see which would work and which monitoring tool would bemost effective in identifying the improvement.

[0224] With respect to the different monitoring tools, some were morehelpful than others. It was found that the EEG was not very sensitive.The Brain Stem Auditory Evoked Response and other evoked potential testswere very insensitive tools for monitoring, because of the length oftime required to perform the test after short-acting medications weregiven in IM or sublingual or nasal spray administration route. TheTranscranial Doppler consistently appeared to give the best indicationas to which medications would work. If an ultrasound showed improvement,the patient invariably also reported improvement in their clinicalsymptoms. These symptoms included not only headache, but also sensationsof confusion, balance disorder, abnormal Romberg or Tandem Gait or otherneurological abnormalities. If the medications showed evidence ofincreasing vasoconstriction on the doppler, the patients who had aheadache, frequently reported improvement in the headache, but aworsening of their confusional state or a worsening of otherneurological symptoms. Those patients were identified as havingimprovement on ultrasound with doppler also showed resolution of theirheadache, but did not show the deterioration in other neurologicaleffects.

[0225] This was completely unexpected. The general approach towardsmigraine and headache has always been that the headache represents avasodilation and frequently a hyperperfusion state. The aura, of course,represents a vasoconstrictive phase. What our results seemed to suggestwas that the doppler, which looks at essentially the area of bloodvessels around the base of the brain, was showing vasoconstriction.Vasoconstrictive medicines would relieve the headache presumably througha similar mechanism, as a vasoconstrictive medication probably relievedcoronary artery disease. It would relieve it by decreasing thevasodilation that occurs downstream from the area we are able todirectly insonate. Unfortunately, if cerebral artery disease is anythinglike coronary artery disease, that downstream dilation represents anattempt by the body to compensate and maintain perfusion to thusbecoming ischemic.

[0226] In Applicant's patient population, all medications which resultedin vasoconstriction, relieved the headache, but caused neurologicaldeterioration. As the medication wore off, as documented by thepatient's clinical symptoms, sonography data, the patient's neurologicalabnormalities improved. Similarly, those medicines which resulted indirect vasodilation such as Hydralazine (Apresoline), Nitroglycerin andother medications all resulted in improvement in the patient's headache,but also resulted in improvement of any other neurological abnormalitiesincluding balance disorders, gait disorders, hemiparesis, abnormalBabinski's and abnormal reflexes.

Observations Noted Concerning Transcranial Dopplers

[0227] A special word about Transcranial Doppler needs to be made. Wefound that morphology of a Transcranial Doppler Artery Ultrasound is asimportant as mean flow velocities. In our patients, as they became morenormal, and as their fixed deficits and neuropsychological abnormalitiesresolved etc., the morphology of the wave form would be similar to thatof an internal carotid artery tracing. We did not find that there wouldbe elevation of flow readings throughout diastole, as is more commonlypublished. It is important to identify that the original normative dataobtained in 1979, used for “Normals” patients with post-traumaticmigraine disorders, “psychogenic seizures”, and the interictal migrainephase may not be appropriate. It is important to note that other labswhich have done less extensive studies of normal versus non-normal, mayhave unknowingly used many patients with a history of migraines orwhiplash headaches.

[0228] Some have not identified the close relationship between degree ofvasospasm and clinical abnormalities. This may be due to less lengthymonitoring or evaluations being carried out by those labs in comparisonto our own. Equally, the trend clinical correlation is a general one.Remembering hemodynamics, it is important to note that if the bloodvessel is constricted, patients do have a limited ability to compensatefor the effects of that vasoconstriction by dilating distally to theconstricted area. Patients will not be abnormal clinically during theearly stages of constriction of an artery. It is only once thedownstream area is no longer able to dilate to a degree enough tomaintain a significant pressure gradient across the vasoconstricted areathat the patient will develop symptoms. It is important to continue tomonitor and treat these patients until the sonographic studies return tonormal and beyond. Realizing that blood vessels constrict across the dayin response to sympathetic nervous system variability, internal steroidrelease, physiological and psychological stress, including thephysiological stress of photic stimulation, driving etc. and thus toobtain an ultrasound at one moment, must be correlated with thepatient's clinical symptoms and any complaints of variability across theday.

[0229] We also found that over time, chronic, untreated patient studiesfrequently falsely appear to normalize with a dropping of mean flowvelocities. This occurs as the body develops compensating mechanisms torelieve the ischemia. Thus morphology becomes extremely important inidentifying those who have ongoing vasoconstrictive disorderintracranially.

[0230] The development of a pattern as time goes on is to have a bluntedupstroke in the systolic portion of the ultrasound, but with an overallmean flow velocity of less than 0.6 meters per second. That blunting,which is also seen in disseminated vascular disease from any cause, ishighly suspicious for severe vasospastic disorder. A computerized EEG orstandard EEG consistent with brain dysfunction or ischemia, and/orneuropsych testing consistent with variability of cognitive injury(especially with fluctuating cognitive deficits across several hours ordays of testing) with ischemia is often helpful as a corroboratingstudy. These are patients who should not be treated initially withNitroglycerin or other potent medications, but should first have othermedications which are direct vasodilators instituted as low doses andslowly advanced as the patient is able to tolerate it. This institutionwith alternative vasodilators, tends to decrease the incidence of apotentially dangerous nitric oxide sensitivity reaction.

[0231] With respect to Nitroglycerin, what we have seen is several timecourses of the effect of Nitroglycerin. The first is an acute effectwhich lasts between 15 and 45 minutes. The method of administrationbeing a patch, pill or sublingual spray determines the rapidity ofabsorption and distribution. It seems to have a lingering effect forapproximately 2 to 3 hours. Nitroglycerin then gets converted into avariety of subsidiary byproducts, all with some vasodilating properties.Each of these medications themselves can accumulate in patients to toxicdoses, and can cause a reactive cerebral vasoconstriction. Thus, it iseasier to maintain patients on intermittent low dose Nitroglycerinapplications, then chronic applications of medication, as the clinicaldata and clinical response to the vasodilator challenge becomesconfused. With respect to Nitric Oxide sensitivity, those patients inApplicant's clinical practice who have not been premedicated with a betablocker, an alpha blocker or a direct vasodilator such as a calciumchannel blocker or an ACE inhibitor, who are given their first dose ofNitric Oxide and developed acute erythema of the nose or face, arehaving a reactive vasoconstriction and distal vasodilation occurring atthe same time. Those patients on Transcranial Doppler Artery Ultrasoundwill have acute spasm of the arteries and active constrictions anddilations may frequently be seen. Those patients may have a seizure or astroke or a blackout spell. This problem can be immediately reversedwith IM Toradol(ketoralac). Toradol in 90 to 120 mg IM doses causesacute vasodilation on ultrasound in most patients. In lower doses, theTranscranial Doppler Artery Ultrasounds generally do not showsignificant changes, but the patient reports a symptomatic improvement.

[0232] IV Toradol in 30 to 60 mg doses does not cause any improvement onTranscranial Doppler Artery Ultrasound, and patients generally report asensation of vertebrogenic syndrome with increase in spaciness,confusion, worsening headache and worsening spasm. Although I have notidentified this directly, their clinical course is that of a developmentof a vasoconstricted vertebral or basilar artery syndrome. This probablyrelates to a carrier drug in the I.V. Toradol solution. Without a changein formulation, Applicant would not recommend the I.V. use of Toradol toreverse acute and life threatening vasospasm or stroke.

[0233] Multiple medications over the last several years have now beentried for the vasodilators. A discussion of these will follow. It shouldbe recognized, that Applicant's patients tend to be the most severecases it our area. Accordingly, for me, the medications that have beenmost effective have also been among the strongest. The less strongmedication will undoubtedly be very helpful in less severe cases. In allcases, as the vasospasm may be subclinical or affecting portions oftheir cognitive abilities that they do not routinely use. patients cannot be considered as reliable in identifying when the vasospasm isresolved. Accordingly, ongoing monitoring of therapy with functionaltests such as EEG or Neuropsych testing and imaging tests likeultrasound are vital for evaluation of response to therapy.

[0234] With respect to Beta Blockers, Inderal (Propranolol), Tenormin(Atenolol), Lopressor (Metoprolol Tartrate) and Normodyne (Labetolol)have all been tried. None of these have been significantly effective atvasodilation. However, when using vasodilators, patients will frequentlynotice waxing and waning of their effectiveness. This is especiallynoticeable in patients who are beginning to be tapered off theirmedications due to good responses, and thus cannot tolerate higher dosesof medications of vasodilators, but still have residual vasospasm. Inthese patients, Inderal has been extremely effective in smoothing outthe sympathetic nervous system excitability that may be seen. The othermedications have not been as effective, although probably are useful inblunting any acute response to Nitroglycerin administration from ahypersensitive Nitric Oxide response, if the patient is prone to such aresponse.

[0235] Alpha blockers have been tried Hytrin (Terazosin) has not beenfound to be effective. Catapress (Clonidine) has been extremelyeffective. Minipress (Prazosin) has been significantly effective andfrequently better tolerated in the long run than Clonidine, although inApplicant's patients, it seems to treat the problem successfully enoughto prevent the symptoms, but not enough to allow complete resolution ofthe vasospasm. Cardura (Doxazosin) has been a relatively mildmedication. Aldomet (Methyldopa) has been useful in some patient.Reserpine has been an extremely effective medication. In the short term,it is helpful due to the parasympathomimetic effect, which tends todecrease the activity of the Sumpathetic nervous system. Later, itsdirect sympatholytic action is very effective. Frequently, a dose needsto be adjusted downward approximately 6-10 weeks after institution oftherapy. It has even been useful in treating migraine induced depressiondue to chronic vasospasm with or without headache in those patients whocould not tolerate other vasodilators. Clonidine has also been useful inthese depressed patients who could not respond to other vasodilatingmedications.

[0236] ACE inhibitors have been tried. With use of ACE inhibitors andconcomitant administration of low dose Nitroglycerin, {fraction(1/10)}th inch once a day to several times a day, most patients may beeventually weaned from the use of oral medications, although Applicantdo tend to maintain them on low dose Nitroglycerin in perpetuity. OtherAngiotensin Converting Enzyme Inhibitors, including Capoten (Captopril),Altace (Ramipril), Lotensin (Benazepril), Monopril (Fosinopril),Prinivil (Lisinopril), Vasotech (Enalapril) and an ACE inhibitor havealso been tried. I suspect that ACE inhibitors work the best due to itsactivity on the Nitric Oxide pathway. It is most effective at reversingthe vasospasm when used in conjunction with low dose nitrates.

[0237] Calcium channel blocker have been tried. The most effective hasbeen Dynacirc (Isradapine). Much less effective have been, in descendingorder of effectiveness, Nifedipine. Nimodopine, Plendil (Felodipine),Dilacor (Diltiazem), Cardene (Nicardipine) and. Norvasc (Amlodopine) andfinally, Verapamil.

[0238] Other agents that deserve special mention include Toradol IM indoses of 90-120 mg. In lower doses., this is not so effective.Unfortunately, due to the new FDA guidelines. Applicant no longer usethis medication in these doses. Hydralazine is effective, but tends tocause significant blood pressure changes in these patients.Interestingly though, Hydralazine tends to improve the morphology of thediastolic flow component dramatically which in view of Hydralazine'seffect on arterioles, bolsters the perspective that the diastolic phaseof the Transcranial Doppler is a good indicator of downstream runoff.

[0239] Psychiatric agents frequency have vasoactive effects. Prozac andother non-vasoconstricting medications are helpful. Those known to causevasoconstriction tend to aggravate the spasm and neurologicalabnormalities. Antipsychotic agents have also been used. Several ofApplicant's patients who ApplicanT will be reporting on later, werepsychotic, and responded well to these medication s and had significantvasospasm identified on ultrasound which improved after theadministration of medication. Of the antipsychotics, Navanne(Thiothixene) has been the most effective. Thorazine (Chlormromazine)has been moderately effective. Respiradol has generally improved thepatient's symptoms but had no significant improvement on ultrasound. Ithas been less well-tolerated in comparison with Thorazine and Navane.Interestingly enough, most of the patients who were placed on Navane,did not continue to require Navane two to three months after startingthe medication, and were able to be weaned from that and had betterresponse to their other vasodilators. In general Navane was used as afirst line drug in patients who had severe elevations of TranscranialDoppler Artery mean flow velocities greater than 1.3, and we wouldgenerally expect 50% improvement in the Transcranial Doppler ArteryUltrasound within a half hour of administering Navane by liquidsolution. The solution was made by stirring 2 mg of Navane in 4 ouncesof water then administered orally. The patients were usually afterwardsplaced on vasodilators such as ACE inhibitors and Calcium channelblockers. Mellaril (Thioridazine) has had no significant effects.

[0240] Of the Anti-epileptic drugs, including Dilantin (Phenytoin),Tegretol (Carbamazepine) and Depakote (Valproate), none of themedications in therapeutic doses have changed the vasospasm, but allhave improved in some patients the EEG abnormalities and theirneurocognitive or neurological complaints.

[0241] Problems

[0242] The approach used in Applicant's clinical practice of over 2,000patients, is the approach of using vasodilators to treat migraineheadache, to cause improvement in closed head injury symptoms, and totreat disorders diverse and including seizures, stroke, syncope,attention deficit disorder, vertigo, autism, depression, psychosis,transient global amnesia. Multiple Sclerosis and Multiple Sclerosis likesyndrome, but not limited to these disorders.

[0243] However, approximately 10% of patients placed onantihypertensives will develop peripheral hypotension before thevasospasm is successfully treated. These patients appear to haveincreased peripheral vasodilation to central vasodilation in response tothe medication.

[0244] In these patients, several approaches may be used. Thepharmacological approach is to mix several medications of differentclasses at submaximal doses to achieve a synergistic response. Analternative approach is to use medications such a Toradol orantipsychotic medications that also dilate primarily the vascular bed ofthe Central Nervous System and not that of the peripheral. In thosepatients, Navane and the antipsychotic of that group, have been found tobe an extremely effective central vasodilator without causing peripheralblood pressure changes. Patients placed on these agents are frequentlyable to tolerate low dose ACE inhibitors. Calcium Channel agents, orother peripheral vasodilators without developing hypotension and stillhave excellent resolution of vasospasm. The structural approach is tosearch for an underlying aggravating problem affecting the sympatheticnervous system. This is usually caused by an injured area of the bodywhich may include joint injuries, disk injuries, nerve injuries, etc.One of Applicant's patients developed severe neurocognitive problems andneuropsych abnormalities, EEG problems and vasospasm, from a CarpalTunnel Syndrome. The correction of that problem, or any other irritantto the Sympathetic Nervous system by blocking the irritant or removingit, may result in a decrease in the autonomic hyperactivity, and animproved response to medication. A third approach is to sympatheticallydenervate the vasculature. This may be partially performed with EpiduralSteroid Injections with or without anaesthetic, Facet or Perifacetblocks, Rhyzolysis, Stellate Ganglion Blocks and Neurolyses and similarprocedures. In Applicant's practice, procedures oriented towards theinnervation of the Carotid arteries tend to cause Anterior and MiddleCerebral artery relaxation. This clinically results in increaseconcentration/memory and decreased mood/personality problems andlanguage problems and other frontal and temporal lobe disorders.Posterior circulation denervation tends to decrease occipital headaches,and improve balance, vertigo, and visual complaints and have secondarycognitive, effects (probably through perforating vessel contributions).Blocks tend to work for a dramatically shorter period of time than doneurolysis procedures.

[0245] Chiropractic procedures may be very helpful as may Biofeedbackand counselling procedures to decrease the Autonomic hyperactivity.These techniques may also be useful adjuncts to treatment in the chronicpatient.

[0246] Stroke. V11

What is claimed is:
 1. A method for the treatment of diseases comprisingvasospasm or other symptom allevietable by smooth muscle relaxation,comprising in combination: a) measuring blood flow in at least one area;b) administering a first dosage of a vasodilator; c) remeasuring bloodflow, and; d) administering a further dosage of a vasodilator, saidfurther dosage being adjusted in response to the remeasured blood flow;e) continuing said treatment over a period of days while titrating saiddosage according to still further measurements of blood flow to maintainoptimal blood flow velocity.
 2. A method according to claim 1 whereinthe symptoms comprise cerebral vasospasm.
 3. A method according to claim1 wherein the measuring comprises a technique selected from the groupconsisting of Transcranial Doppler (TCD), quantitativeelectroencephalogram and determining relative vessel diameter.
 4. Amethod according to claim 1 wherein the blood flow is measured as MeanFluid Velocity (MFV) in at least one intracranial vessel.
 5. A methodaccording to claim 4 wherein the MFV rises above about 0.4 meters/minuteduring vasospasms.
 6. A method according to claim 1 wherein thetreatment is continued for from about 5 to 250 weeks.
 7. A methodaccording to claim 1 wherein the vasodilator is selected from the groupconsisting of Nitroglycerin in pill, patch, ointment, cream, inhaler,spray and other forms, Nitroglycerin equivalents and substitutes, suchas p.o. clonidine, Dynacirc (isradipine), hydrazine, nifedipine, andmedicines from the empirical group of medications which have the commoncharacteristic of causing smooth muscle relaxation and whichsystemically reduce pulmonary capillary wedge pressure, and combinationsof the foregoing.
 8. A method according to claim 1 wherein the diseaseis selected from the group consisting of whiplash, closed head injurywith vasospasm, attention deficit disorder with vasospasm, migraine withinter-octal evidence of vasospasm, syncope or blackout spells of unknownaetiology with evidence of vasospasm, seizure with evidence ofvasospasm, and dementia with evidence of vasospasm, concussion andpost-concussion syndrome with evidence of vasospasm, migraine,sympathetic vasospasm associated with breast implants, and cerebralvasospasm.
 9. A method according to claim 1 wherein the disease isselected from the group consisting of dyslexia, memory disturbances,depression, psychosis, reflex sympathetic dystrophy, mood disorders andsensory motor disorders; transient ischemic attack (TIA), pseudoseizure,hemibalism, and stroke; tremor, Parkinson's disease, torticollis,electrical shock trauma, attention deficit disorder, concussion and postconcussion syndrome, in which vasospasm can be detected.
 10. A method ofclaim 1 wherein the patient treated initially presents with transient orcontinuous TCD Mean Flow Velocities (MFV) of greater than 0.1 meter persecond.
 11. A method of treatment of intracranial vasospasms comprisingintermittent application of a vasodilator and reducing dosage as thevasospasms reduce in frequency and/or severity.
 12. A method of claim 1wherein the treatment is applied to a patient who initially presentswith transient or continuous TCD Mean Flow Velocities (MFV) of greaterthan 0.3 meters per second.
 13. Vasodilator delivery systems speciallyadapted to deliver about 5 to 25% of conventional dosage of vasodilatorsand marked with the appropriate DRG and/or ICD 9th. codes and/orinstructions for titrating or tapering their use, to facilitate theirproper application for treatment of diseases involving vasospasms.
 14. Adelivery system according to claim 13 adapted for transdermal delivery.15. A delivery system according to claim 13 adapted for delivery ofabout 0.02 to 20 milligrams per day (Nitroglycerine equivalent) ofvasodilator.
 16. A delivery system according to claim 13 adapted fordelivery of a vasodilator selected from the group comprisingNitroglycerin in pill, patch, ointment, cream, inhaler, spray and otherforms, Nitroglycerin equivalents and substitutes, comprising p.o.clonidine, Dynacirc (isradipine), hydrazine, nifedipine, and/or othermedicines selected from the empirical group of medications which havethe common characteristic of causing smooth muscle relaxation and/orwhich systemically reduce pulmonary capillary wedge pressure, andcombinations of the foregoing.
 17. A method according to claim 1 whereinthe disease is selected from the group consisting of fibromyalgia,cardiac disease, gastric disorders and other systemic disorders,psychosis, other psychiatric disease, attention deficit disorder,comprising vasospasm as a component.
 18. A method according to claim 1wherein the disease is selected from the group consisting of systemicdisorders comprising vasospasm as a component.
 19. A method fordiagnosing and treating a disease caused at least partially byinsufficient cerebral perfusion, comprising in combination: testing forpresence of a continued diastolic flow beyond end diastolic velocity asan indication of vasospasm, administering a vasospasm-reducing dosage ofa medicine selected from the empirical group of medications which havethe common characteristic of causing smooth muscle relaxation and/orwhich reduce pulmonary capillary wedge pressure, repeating said testingover time and titrating said dosage to minimize occurrence and severityof said vasospasms.
 20. Each invention substantially as describedherein.